Pd(ii)-catalyzed enantioselective c-h arylation of free carboxylic acids

ABSTRACT

The invention includes procedures for stereoselective β-acylation of carboxylic acids having a β-carbon atom. For example, stereoselective acylation procedures include the following reactions: (I)

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the priority of U.S. provisional applicationSer. No. 62/659,866, filed Apr. 19, 2018, the disclosure of which isincorporated by reference herein in its entirety.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under grant numberGM084019 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

BACKGROUND

Desymmetrization through C—H activation holds the potential to become abroadly useful chiral technology due to the widespread presence ofsymmetric prochiral C(sp³)—H bonds in the majority of organicmolecules.¹ Pd(II)-catalyzed enantioselective intermolecular C(sp³)—Hactivation was recently made possible by a combination of weaklycoordinating directing group and chiral bidentate ligand.^(2,3,4,5) Thisstrategy was firstly demonstrated by the development of N-perfluoroarylamide-directed enantioselective C—H cross-coupling of α-quaternarycyclopropanecarboxamides using mono-N-protected amino acids (MPAA) asthe chiral ligands.^(2a) Recently, chiral bidentate quinoline ligandswere developed to realize enantioselective functionalization ofmethylene C(sp³)—H bond of acyclic N-perfluoroaryl carboxamides toconstruct β-chiral centers,^(2c) while bidentate oxazoline ligandsenabled enantioselective C(sp³)—H functionalization of gem-dimethyl ofN-perfluoroaryl or methoxy carboxamides for the construction of a-chiralcenters.^(2d) However, substrates in these reactions requirepre-installed directing groups which need to be removed after C—Hfunctionalization. Following the same notion of achieving protectinggroup free synthesis,⁶ we embarked on the development ofenantioselective C—H activation of carboxylic acids without usingexogenous directing group.

SUMMARY

The invention is directed, in various embodiments, to procedures forstereoselective β-arylation of carboxylic acids having a β-hydrogenatom. For example, the invention can provide A method of stereoselectivearylation of a β-carbon atom of a cyclopropanecarboxylic acid having aβ-hydrogen atom, the cyclopropropanecarboxylic acid having either anα-substituent or having no α-substituent, comprising contacting thecyclopropanecarboxylic acid and an aryl iodide in the presence of acatalytic quantity of a Pd(II) salt, a molar equivalent or more on anAg(I) basis of an Ag(I) salt, and a molar equivalent or more of a base,in 1,1,1,3,3,3-hexafluoroisopropanol solvent, in the presence of ansingle enantiomer, either (R) or (S), of an acetyl-protected aminoethylamine (APAA) ligand of formula

wherein Ac is acetyl, each R is independently selected methyl or ethyl,or the two R groups together with the nitrogen atom to which they arebonded form a 4- to 6-membered heterocyclyl ring; and wherein R¹ is anunsubstituted or substituted benzyl group, or wherein R¹ is a(C₃-C₄)-alkyl group;

to stereoselectively provide a β-aryl-cyclopropanecarboxylic acid,wherein the arylated β-carbon atom of the β-aryl-cyclopropanecarboxylicacid product, when no α-substituent is present is of an (R) or (S)single enantiomeric configuration, respectively, and when anα-substituent is present is of an (S) or (R) single enantiomericconfiguration, respectively; an aryl group introduced being disposed cisto the carboxylic acid group of the cyclopropanecarboxylic acid.

A substrate cyclopropanecarboxylic acid can be of formula

wherein Rα can be hydrogen (i.e., termed an α-unsubstitutedcyclopropanecarboxylic acid herein), or can be a substituent, e.g., analkyl, aryl, alkaryl, or heteroaryl group and the like, any of which canbe further substituted with organic functional groups other than acarboxylic acid group (i.e., termed an α-substitutedcyclopropanecarboxylic acid herein). If no other substituents arepresent, this precursor is achiral. When the stereoselective arylationreaction of the invention is carried out, a product of formula

is obtained, the introduced aryl group being inserted cis to thecarboxylic acid group, and stereoselectively such that when the ligandused is of the (S) absolute configuration, the β-carbon atom of theproduct from the unsubstituted cyclopropanecarboxylic acid precursorbearing an aryl group is of the (S) absolute configuration at thatchiral center; and the β-carbon atom of the product from the substitutedcyclopropanecarboxylic acid precursor bearing an aryl group is of the(R) absolute configuration at that chiral center.

The designation of the absolute configuration of the productβ-arylcyclopropanecarboxylic acid as (S) or (R) in the product variesfrom the unsubstituted to the substituted case due to the change in thepriority of groups bonded to the β-carbon atom under theCahn-Ingold-Prelog group priority rules for assigning absoluteconfiguration of (R) or (S) to a chiral center. The aryl group isintroduced to the β-carbon atom via a Pd-ligand-substrate complex thatis analogous between α-unsubstituted and α-substituted precursorcyclopropanecarboyxlic acids, but the presence of the α-substituentalters the naming protocol to provide the opposite (R) or (S)configuration assignment to that of the α-unsubstituted reactionproduct.

In other embodiments, the invention can provide a method ofstereoselective arylation of a β-carbon atom of 2-phthalimidoisobutryicacid, comprising contacting the 2-phthalimidoisobutryic acid and an aryliodide in the presence of a catalytic quantity of a Pd(II) salt, a molarequivalent or more on an Ag(I) basis of an Ag(I) salt, and a molarequivalent or more of a base, in 1,1,1,3,3,3-hexafluoroisopropanol(HFIP) solvent, in the presence of an single enantiomer, either (R) or(S), of an acetyl-protected aminoethyl amine (APAA) ligand of formula

wherein Ac is acetyl, each R is independently selected methyl or ethyl,or the two R groups together with the nitrogen atom to which they arebonded form a 4- to 6-membered heterocyclyl ring; and wherein R¹ is anunsubstituted or substituted benzyl group, or wherein R¹ is a(C₃-C₄)-alkyl group;

to stereoselectively provide a β-aryl-2-phthalimidoisobutryic acid,wherein the β-aryl-2-phthalimidoisobutryic acid product is of an (R) or(S) single enantiomeric configuration, respectively.

In carrying out a method of the invention, the APAA ligand can be offormula

the Pd(II) salt can be Pd(OAc)₂; the carbonate base can be Na₂CO₃, orthe Ag(I) salt can be Ag₂CO₃, or both.

For instance, the Pd(II) salt can be present at about 10 mole %, theligand can be present at about 20 mole %, or both. The reaction can becarried out in HFIP, for example at about 80° C.

DETAILED DESCRIPTION

Directed functionalization of C(sp³)—H bonds of carboxylic acids withoutinstalling external directing group remains a significant challengedespite recent advances using pyridine/quinoline and MPAA ligands.⁷These difficulties escalate in the development of enantioselective C—Hactivation reactions. First, C(sp³)—H activation reactions of freecarboxylic acids suffer from low reactivity due to the weak directingability of the carboxyl groups. Second, the conformation of themetal-carboxylate complex is more flexible than that of the metal-amidedirecting group complex, which could cause problems for stereocontrol.Indeed, our previously developed bidentate acetyl-protected aminoethylquinoline ligand only had limited success with a single specialsubstrate, phthalyl-protected 1-aminocyclopropanecarboxylic acid.^(2c)Therefore, we set out to develop a new type of ligands that couldachieve more effective enantioselective control with free carboxylicacids. Herein we report the development of ethylenediamine derivedchiral ligand that enables enantioselective C—H arylation of a broadrange of cyclopropanecarboxylic acid, as well as the 2-aminoisobutyricacid.

Development of asymmetric syntheses of chiral cyclopropane⁸ continues toattract attention because of their prevalence in biologically activenatural products and pharmaceuticals.⁹ We, therefore, selectedcyclopropanecarboxylic acid as a model substrate for our liganddevelopment. Notably, our previous enantioselective C—H coupling ofcyclopropanecarboxamides with Ar-Bpin requires the presence ofα-quaternary carbon centers.^(2a,10)

Based on our previous chiral bidentate MPAA, quinoline, and oxazolineligands, acetyl-protected amino group (NHAc) is a privileged moiety ofchiral ligands for promoting C—H cleavage. We, therefore, decided tokeep this motif intact while replacing the carboxyl, quinoline, andoxazoline with other a-donor for chelation. Specifically, we synthesizeda series of acetyl-protected aminoethyl amine (APAA) ligands to achieveenantioselective C(sp³)—H functionalization of free carboxylic acids(Scheme 1, Table 1). First, various N-alkyl tertiary amine ligands weretested. Despite moderate background reaction in the absence of ligands(Table 1), effective binding of the ligands and possible ligandacceleration afforded significant enantioselectivity. Comparison of theresults from L1 to L4 indicates that steric hindrance on the tertiaryamine reduces the reactivity. For example, diisopropylamine ligand onlyprovided 8% yield of the product with almost no enantioselectivity.Cyclic amine ligand L5 and L6 are inferior in both reactivity andenantioselectivity. Notably, replacing acetyl with other protectinggroups led to a complete loss of reactivity (L7-L10). Ligands withdifferent side chains were also examined. Among different substituents,benzyl group (L1) gave the best yield of 82% and highest er of 97:3,while, isopropyl (L11), sec-butyl (L12) tert-butyl group (L13) andisobutyl (L14) gave slightly lower yield and enantioselectivity.Surprisingly, the ligand with phenyl group (L15) provided only 20% yieldand low enantioselectivity. Less hindered homobenzyl group (L16) alsoreduced the reactivity and selectivity. Hence, we focused on themodification of the benzyl group. Introducing substituent to the paraand ortho position on the phenyl group, as well as replacing phenyl withthe naphthalenyl group lowered the yield (L17-L21). Finally, ourprevious three classes of chiral ligands all gave poor yields orenantioselectivity (L22-L23).

With the high-yielding and highly selective conditions in hand, weexamined the scope of aryl iodides (Table 2). Majority of the aryliodides containing electron-withdrawing and electron-donating groupafforded desired products in good yields and high enantioselectivities(up to 98:2 er). Aryl iodides bearing electron-withdrawing groups suchas para-methoxycarbonyl (3a), para-acetyl (3b), para-trifluoromethyl(3d), meta-trifluoromethyl (3k) and ortho-methoxycarbonyl (3t) gaveslightly higher yields than other aryl iodides. However, aryl iodidewith a nitro group (3c) gave 53% yield of the product with 90:10 er.lodobenzonitrile (3e) also afforded a lower yield but with highenantioselectivity. Notably, aryl iodides containing bromo (3h),phosphonate (3j), and aldehyde (3m) afforded the desired products inhigh yields and good enantioselectivity. Besides substituted phenyliodides, heteroaryl iodides such as 2-acetyl-5-iodothiophene (3u) and5-iodo-2-furaldehyde (3v) could also be tolerated in this reactionproviding moderate yields and high er. The reaction using methyliodobenzoate as the limiting reagent and a lower loading of silver saltalso afforded a higher yield and enantioselectivity (3a).

The APAA ligand shown, of the (S) absolute configuration, yielded thecyclopropane-carboxylic acid of the (S) configuration at the arylatedcarbon atom, and yielded the (S)-enantiomer of the arylatedphthalimidylisobutyric acid. The opposite enantiomer of the chiralligand shown in Scheme 1 was also prepared and shown to be compatiblewith these substrates, albeit giving the corresponding products with theopposite enantiomer (the mirror image).

A wide range of a-substituted cyclopropanecarboxylic acids are alsotested using methyl iodobenzoate as the coupling partner (Table 3).1-Aryl-1-cyclopropanecarboxylic acids (5a-d), which are an importantmotif in pharmaceutical chemistry,¹¹ were arylated to give the desiredproducts in excellent yield and enantioselectivity. Interestingly,C(sp²)—H arylation of the a-phenyl groups did not occur. Chloro (5b),bromo (5c) and trifluoromethyl (5d) substituents on the phenyl group ofsubstrates were all well tolerated in this reaction. α-Alkylcyclopropanecarboxylic acids are also suitable substrates for thisreaction. Arylation of α-ethyl (5e), butyl (5f), and chloropentyl (5h)cyclopropanecarboxylic acids under 60° C. afforded the mono-arylatedproducts in good yields and er. Surprisingly, α-phenylpropylsubstitution reduced the yield to 58% (5g). Although α-Benzyl containingsubstrates (5i and 5j) decomposed under these conditions, replacement ofAg₂CO₃ with AgOAc provided desired products in moderate yield and highenantioselectivity. Benzyl-protected 1-hydroxymethyl (5k) andphthalyl-protected 1-aminomethyl cyclopropanecarboxylic acids (5l)provided good yield and excellent enantioselectivity. These β-hydroxyland β-amino-cyclopropanecarboxylic acid motifs are recurrent structuresin bioactive molecules.¹²

TABLE 1 Ligand Screening for Enantioselective Arylation ofCyclopropanecarboxylic Acid^(a,b)

No Ligand 30% yield ^(a)Conditions: 1 (0.2 mmol), 2a (2.0 equiv),Pd(OAc)₂ (10 mol %), ligand (20 mol %), Ag₂CO₃ (1.5 equiv), Na₂CO₃ (1.5equiv), HFIP (0.25 mL), 80 °C., air, 16 h. ^(b 1)H NMR yields, usingCH₂Br₂ as an internal standard.

TABLE 2 The Scope of Aryl Iodides for Enantioselective Arylation ofCyclopropanecarboxylic Acid^(a,b)

^(a)Conditions 1 (0.2 mmol), 2 (2.0 equiv), Pd(OAc)₂ (10 mol %), L1 (20mol %), Ag₂CO₃ (1.5 equiv), Na₂CO₃ (1.5 equiv), HFIP (0.25 mL), 80° C.,air, 16 h. ^(b)Isolated yields. ^(c)Conditions 2a (0.2 mmol), 1 (2.0equiv), Pd(OAc)₂ (10 mol %), L1 (20 mol %), Ag₂CO₃ (1.0 equiv), Na₂CO₃(1.5 equiv), HFIP (0.25 mL), 80° C., air, 16 h. ^(d)Using AgOAc (3.0equiv) instead of Ag₂CO₃ (1.5 equiv), NaHCO₃ (1.5 equiv) instead ofNa₂CO₃ (1.5 equiv). ^(f)Using 2 (1.5 equiv).

TABLE 3 Enantioselective Arylation of Substituted CyclopropanecarboxylicAcid^(a,b)

^(a)Conditions 4 (0.2 mmol), 2a (2.0 equiv), Pd(OAc)₂ (10 mol %), L1 (20mol %), Ag₂CO₃ (1.5 equiv), Na₂CO₃ (1.5 equiv), HFIP (0.25 mL), 80° C.,air, 16 h. ^(b)Isolated yields. ^(c)60° C. ^(d)Using AgOAc (3.0 equiv)instead of Ag₂CO₃ (1.5 equiv), NaHCO₃ (1.5 equiv) instead of Na₂CO₃ (1.5equiv), 60° C.

The performance of this new chiral ligand was further tested in theenantioselective arylation of phthalyl-protected 2- aminoisobutyricacids via desymmetrization of the gem-dimethyl (Table 4). Such reactioncould provide a simple avenue for the synthesis of diverse chiralα-amino acids.

TABLE 4 Enantioselective Arylation of 2-aminoisobutyric Acid^(a,b)

^(a)Conditions: 1 (0.1 mmol), 7 (2.5 equiv), Pd(OAc)₂ (10 mol %), L1 (20mol %), AgOAc (3.0 equiv), NaHCO₃ (1.5 equiv), HFIP, 80 °C., air, 24 h.^(b)Isolated yields. ^(c)Isolated as the corresponding methyl ester.

While aryl iodides bearing different substituents gave similar yields ofproducts, the enantioselectivity varied. Electron-neutralgroup-substituted aryl iodides gave good enantioselectivity, aryliodides containing electron-withdrawing groups (7a, 7b, and 7g) providedlower er. Since aryl iodides are not involved in the enantio-determiningC—H activation step, it is possible that one of the chiral palladacycleintermediates from this particular substrate is less reactive in theoxidation addition step with aryl iodide, thereby contributing to theenantioselectivity partially. A further extensive mechanistic study willbe conducted to rationalize this observation.

To further demonstrate the utility of this new methodology, a late-stageC—H functionalization of a promising drug candidate on neurologicaldisorders, Itanapraced,¹³ was performed. The reaction proceededsmoothly, and the modified molecule was obtained in high yield and withexcellent enantioselectivity (eq 1).

In summary, we have developed a new class of chiral acetyl-protectedaminoethyl amine ligands which enable the enantioselective C—Hactivation of free carboxylic acids without using exogenous directinggroups. Enantioselective C—H arylation of simple cyclopropanecarboxylicacid and phthalyl-protected 2-aminoisobutyric acid provides a newsynthetic disconnection for asymmetric synthesis of diverse chiralcarboxylic acids. The successful design of this new ligand to match theweakly coordinating carboxylic acid for stereocontrol offers a frameworkfor understanding the chiral induction in sp³ C—H activation.

EXAMPLES

Carboxylic acids were obtained from the commercial sources orsynthesized following literature procedures. Alkyl iodides were obtainedfrom the commercial sources. Solvents were obtained from Sigma-Aldrich,Oakwood, and Acros and used directly without further purification.Analytical thin layer chromatography was performed on 0.25 mm silica gel60-F254. Visualization was carried out with UV light and BromocresolGreen Stain. ¹H NMR was recorded on Bruker DRX-600 instrument (600 MHz).Chemical shifts were quoted in parts per million (ppm) referenced to theliterature values of tetramethylsilane. The following abbreviations (orcombinations thereof) were used to explain multiplicities: s=singlet,d=doublet, t=triplet, q=quartet, p=pentet, m=multiplet, br=broad.Coupling constants, J, were reported in Hertz unit (Hz). ¹³C NMR spectrawere recorded on Bruker DRX-600 instrument (150 MHz), and were fullydecoupled by broad band proton decoupling. Chemical shifts were reportedin ppm referenced to either the center line of a triplet at 77.0 ppm ofchloroform-d or the center line of a multiplet at 29.84 ppm ofacetone-d⁶. High-resolution mass spectra (HRMS) were recorded on anAgilent Mass spectrometer using ESI-TOF (electrospray ionization-time offlight). Enantiomeric ratios (er) were determined on an Agilent SFCsystem or Waters SFC system using commercially available chiral columns.

Standard abbreviations for chemical groups such as are well known in theart are used; e.g., Me=methyl, Et=ethyl, i-Pr=isopropyl, Bu=butyl,t-Bu=tert-butyl, Ph=phenyl, Bn=benzyl, Ac=acetyl, Bz=benzoyl, and thelike.

Aryl groups are cyclic aromatic hydrocarbons that may or may not includeheteroatoms in the ring. An aromatic compound, as is well-known in theart, is a multiply-unsaturated cyclic system that contains 4n+2πelectrons where n is an integer. Examples include phenyl, naphthyl,furyl, thienyl, pyridyl, and similar groups. Aryl groups can beunsubstituted, or can be substituted with alkyl, halo, haloalkyl,alkoxyl, haloalkoxyl, carboxaldehyde, carboxyester, and similarsubstituents.

An aryl iodide, as the term is used herein, refers to a compoundcomprising one or more aryl rings, wherein an iodo group is covalentlybound to an aryl ring.

The isomers resulting from the presence of a chiral center comprise apair of non-superimposable isomers that are called “enantiomers.” Singleenantiomers of a pure compound are optically active, i.e., they arecapable of rotating the plane of plane polarized light. Singleenantiomers are designated according to the Cahn-Ingold-Prelog system.The priority of substituents is ranked based on atomic weights, a higheratomic weight, as determined by the systematic procedure, having ahigher priority ranking. Once the priority ranking of the four groups isdetermined, the molecule is oriented so that the lowest ranking group ispointed away from the viewer. Then, if the descending rank order of theother groups proceeds clockwise, the molecule is designated as having an(R) absolute configuration, and if the descending rank of the othergroups proceeds counterclockwise, the molecule is designated as havingan (S) absolute configuration. In the example in the Scheme below, theCahn-Ingold-Prelog ranking is A>B>C>D. The lowest ranking atom, D isoriented away from the viewer. The solid wedge indicates that the atombonded thereby projects toward the viewer out of the plane of the paper,and a dashed wedge indicates that the atom bonded thereby projects awayfrom the viewer out of the plan of the paper, i.e., the plane “of thepaper” being defined by atoms A, C, and the chiral carbon atom for the(R) configuration shown below.

A carbon atom bearing the A-D atoms as shown above is known as a“chiral” carbon atom, and the position of such a carbon atom in amolecule is termed a “chiral center.” Compounds of the invention maycontain more than one chiral center, and the configuration at eachchiral center is described in the same fashion.

Substrate Structures Aryl Iodides

α-Substituted Cyclopropanecarboxylic Acids

Preparation of Ligands

Ligand L1-18, L20-21 were synthesized using the following procedure fromcorresponding commercially available Boc-protected amino acids. L19 wassynthesized from Boc-protected (2,6-diphenylphenyl)alanine which wassynthesized following reported procedure¹

The corresponding Boc-protected amino acid (S1) (5 mmol),dimethylammonium chloride (11 mmol, 0.90 g) and benzotriazol-1-olhydrate (HOBt) (5 mmol, 0.77 g) were added to a round bottom flaskequipped with a magnetic stir bar. The solid mixture was dissolved inDCM (50 mL), and 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimidehydrochloride (EDC) (6 mmol, 1.15 g) was added at 0° C. The resultingsolution was stirred at 0° C. as N-ethyl-N,N-diisopropylamine (DIPEA)(12 mmol, 1.55 g, 2.09 ml) was added slowly. The reaction solution wasallowed to warm to r.t. and stirred for about 3 h, after which thesolution was poured into a separatory funnel, diluted to 150 mL withadditional DCM, and washed with approximately 25 mL of 10% w/w aqueouscitric acid. The organic layer was separated and subsequently washedwith 25 mL each of saturated aqueous NaHCO₃ and brine. The organics weredried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo toprovide corresponding amide (S2) which could be directly used in thenext step without further purification.

To the Boc-protected amino amide (S2) was added 4 N HCl/dioxane solution(5 ml). The resulting solution was stirred at room temperature for 2 h.Then, the volatile components were evaporated in vacuo, and the residuewas subsequently used in the following reduction step.

To a solution of S3 in THF (10 ml) was added a solution of LiAlH₄ in THF(2.4 M, 3.12 ml, 7.5 mmol) dropwise under N₂ at 0° C. Then, the mixturewas heated to reflux for 12 h, before being cooled down and diluted withether. The mixture was cooled to 0° C., and 0.28 ml of water was addedslowly followed by 15% w/w NaOH aqueous solution (0.28 ml) and water(0.84 ml). The resulting suspension was then warmed to room temperatureand stirred for 15 min before MgSO₄ was added. The mixture was stirredfor additional 15 min before filtration. The filtrate was collected, andthe solvent was removed in vacuo to provide diamine compound (S4) whichcould be used in next step without purification.

To a solution of the synthesized diamine compound (S4) in DCM (10 ml)was added acetyl chloride (10 mmol, 0.78 g, 0.71 ml) at 0° C. Then thesolution was stirred at room temperature for 2 h. The volatilecomponents were evaporated in vacuo, and the residue was dissolved in 10ml of water. The resulting solution was extracted with ether (10 ml ×3),then the aqueous phase was alkalized with 15% w/w NaOH aqueous solutionuntil pH>13. The alkalized mixture was extracted with ether (10 ml ×3),and the organic layers were concentrated to provide the desired APAALigand. The compounds were usually pure enough for subsequentPd-catalyzed C—H functionalization. Further purification could beconducted by recrystallization or reversed phase flash column.

(S)-N-(1-(dimethylamino)-3-phenylpropan-2-yl)acetamide (L1)

L1 was synthesized following the standard procedure, and could bepurified by recrystallized to provide white solid.¹H NMR (600 MHz,CDCI₃) δ7.29 (t, J=7.5 Hz, 2H), 7.22 (tt, J=6.9, 1.5 Hz, 1H), 7.18 (d,J=7.2 Hz, 2H), 5.56 (br-d, J=8.4 Hz, 1H, N—H) 4.22-4.16 (m, 1H), 2.97(dd, J=13.8, 4.8 Hz, 1H), 2.84 (dd, J=13.8, 6.6 Hz, 1H), 2.29 (dd,J=12.6, 9.0 Hz, 1H), 2.19 (s, 6H), 2.16 (dd, J=12.3, 5.7 Hz, 1H), 1.96(s, 3H); ¹³C NMR (150 MHz, CDCI₃) δ170.27, 137.85, 129.85, 128.45,126.52, 61.56, 48.28, 45.70, 38.59, 23.72.

(S)-N-(1-(ethyl(methyl)amino)-3-phenylpropan-2-yl)acetamide (L2)

The corresponding Boc-protected amino amide was synthesized usingethylmethylamine (6 mmol). Then, following standard procedure, L2 wasobtain as pale-yellow solid, which was used without furtherpurification. ¹H NMR (600 MHz, CDCI₃) δ7.29 (t, J=7.8 Hz, 2H), 7.23-7.18(m, 3H), 5.76 (br, 1H, N—H), 4.22-4.17 (m, 1H), 2.98 (dd, J=13.8, 5.4Hz, 1H), 2.84 (dd, J=13.6, 6.9 Hz, 1H), 2.48-2.43 (dq, J=12.6, 7.2 Hz,1H), 2.41-2.36 (m, 2H), 2.26 (dd, J=12.6, 6.0 Hz, 1H), 2.19 (s, 3H),1.96 (s, 3H), 1.00 (t, J=7.2 Hz, 3H); ³C NMR (150 MHz, CDCI₃) δ170.29,137.99, 129.78, 128.45, 126.50, 59.02, 51.53, 48.24, 41.72, 38.72,23.70, 12.00.

(S)-N-(1-(diethylamino)-3-phenylpropan-2-yl)Acetamide (L3)

The corresponding Boc-protected amino amide was synthesized according toreported procedure.² Then, following standard procedure, L3 was obtainas pale-yellow solid, which was used without further purification. ¹HNMR (600 MHz, CDCI₃) δ7.29 (t, J=7.5 Hz, 2H), 7.22-7.19 (m, 3H), 5.7s(br-d, J=3.6 Hz, 1H, N—H), 4.16-4.11 (m, 1H), 2.96 (dd, J=13.8, 5.4 Hz,1H), 2.86 (dd, J=13.8, 6.6 Hz, 1H), 2.56-2.45 (m, 4H), 2.40 (dd, J=12.3,8.1 Hz, 1H), 2.36 (dd, J=12.3 6.3 Hz, 1H), 1.94 (s, 3H), 0.95 (t, J=7.2Hz, 6H); ¹³C NMR (150 MHz, CDCI₃) δ170.24, 138.26, 129.65, 128.39,126.39, 55.43, 48.70, 47.03, 38.74, 23.68, 11.68.

(S)-N-(1-(diisopropylamino)-3-phenylpropan-2-yl)acetamide (L4)

The corresponding Boc-protected amino amide was synthesized according toreported procedure.³ Then, following standard procedure, L4 was obtainas pale-yellow solid, which was used without further purification. ¹HNMR (600 MHz, CDCI₃) δ7.29-7.26 (m, 2H), 7.21-7.18 (m, 3H), 5.68 (br-d,J=4.8 Hz, 1H, N—H), 4.04-3.98 (m, 1H), 3.00-2.94 (m 3H), 2.87 (dd,J=8.1, 6.3 Hz, 1H), 2.46 (dd, J=13.2, 6.6 Hz, 1H), 2.41 (dd, J=13.4, 8.7Hz, 1H), 1.93 (s, 3H), 0.96 (d, J=7.2 Hz, 6H), 0.95 (d, J=6.6 Hz, 6H);¹³C NMR (150 MHz, CDCI₃) δ170.37, 138.69, 129.56, 128.37, 126.30, 49.38,47.93, 47.56, 38.91, 23.67, 21.68, 20.31.

(S)-N-(1-(azetidin-1-yl)-3-phenylpropan-2-yl)acetamide (L5)

The corresponding Boc-protected amino amide was synthesized usingazetidine (20 mmol). Then, following standard procedure, L5 was obtainas pale-yellow solid, which was used without further purification.¹H NMR(600 MHz, CDCI₃) δ7.30-7.27 (m, 2H), 7.21 (tt, J=7.5, 1.4 Hz, 1H),7.19-7.17 (m, 2H), 5.69 (br-d, J=6.0 Hz, 1H, N—H), 4.08-4.02 (m, 1H),3.24-3.19 m, 4H), 2.89 (dd, J=13.8, 6.0 Hz, 1H), 2.78 (dd, J=13.8, 7.2Hz, 1H), 2.42 (ABq-d, J_(AB)=12.4 Hz, Δδ=0.02, J₃=6.9, 5.4 Hz, 2H), 2.06(p, J=7.2 Hz, 2H), 1.95 (s, 3H); ¹³C NMR (150 MHz, CDCI₃) δ169.93,138.10, 129.62, 128.48, 126.50, 61.45, 56.17, 49.13, 38.65, 23.72,18.05.

(S)-N-(1-phenyl-3-(pyrrolidin-1-yl)propan-2-yl)acetamide (L6)

The corresponding Boc-protected amino amide was synthesized according toreported procedure.⁴ Then, following standard procedure, L6 was obtainas pale-yellow solid, which was used without further purification. ¹HNMR (600 MHz, CDCI₃) δ7.29 (t, J=7.5 Hz, 2H), 7.23-7.18 (m, 3H), 5.63(br-d, J=4.2 Hz, 1H, N—H), 4.23-4.17 (m, 1H), 2.97 (dd, J=13.5, 5.1 Hz,1H), 2.85 (dd, J=13.5, 6.9 Hz, 1H), 2.53-2.50 (m, 3H), 2.47-2.43 (m,2H), 2.36 (dd, J=12.6, 6.0 Hz, 1H), 1.96 (s, 3H), 1.75-1.72 (m, 4H); ¹³CNMR (150 MHz, CDCI₃) δ170.14, 138.02, 129.85, 128.42, 126.47, 58.11,54.36, 49.46, 38.75, 23.77, 23.72.

(S)-N-(1-(dimethylamino)-3-phenylpropan-2-yl)pivalamide (L7)

The corresponding diamine S3 was acylated with pivaloyl chloride (10mmol, 1.20 g, 1.22 ml) to provide L7 as pale-yellow solid, which wasused without further purification. ¹H NMR (600 MHz, CDCI₃) δ7.28 (t,J=7.5 Hz, 2H), 7.21 (tt, J=7.5, 1.5 Hz, 1H), 7.19-7.15 (m, 2H), 5.83(br-d, J=5.4 Hz, 1H, N—H), 4.14-4.09 (m, 1H), 2.97 (dd, J=13.5, 5.1 Hz,1H), 2.88 (dd, J=13.2, 6.6 Hz, 1H), 2.29 (dd, J=12.3, 8.1 Hz, 1H),2.21-2.18 (m , 7H), 1.14 (s, 9H); ¹³C NMR (150 MHz, CDCI₃) δ178.63,138.04, 129.91, 128.37, 126.46, 61.47, 48.14, 45.69, 38.89, 38.43,27.67.

(S)-N-(1-(dimethylamino)-3-phenylpropan-2-yl)benzamide (L8)

The corresponding diamine S3 was acylated with benzoyl chloride (7.5mmol, 1.05 g, 0.87 ml) to provide L7 as pale-yellow solid, which wasused without further purification. ¹H NMR (600 MHz, CDCI₃) δ7.74-7.73(m, 2H), 7.48 (tt, J=7.5, 1.5 Hz, 1H), 7.42 (t, J=7.5 Hz, 2H), 7.31-7.29(m, 2H), 7.24-7.22 (m, 3H), 6.37 (br-d, J=4.8 Hz, 1H, N—H), 4.37-4.32(m, 1H), 3.14 (dd, J=13.5, 4.5 Hz, 1H), 2.99 (dd, J=13.5, 6.9 Hz, 1H),2.42 (dd, J=12.0, 9.0 Hz, 1H), 2.27 (dd, J=12.6, 6.0 Hz, 1H), 2.22 (s,6H); ¹³C NMR (150 MHz, CDCI₃) δ167.69, 137.87, 135.05, 131.50, 129.99,128.67, 128.49, 127.07, 126.57, 61.36, 48.71, 45.72, 38.49.

Tert-butyl (S)-(1-(dimethylamino)-3-phenylpropan-2-yl)carbamate (L9)

The corresponding diamine S3 was acylated with Boc₂O (7.5 mmol, 1.64 g)to provide L9 as white solid, which was used without furtherpurification. ¹H NMR (600 MHz, CDCI₃) δ7.28 (t, J=7.5 Hz, 2H), 7.22-7.18(m, 3H), 4.67 (br, 1H, N—H), 3.87 (br, 1H), 2.94-2.92 (br-m, 1H), 2.83(dd, J=13.5, 6.3 Hz, 1H), 2.28-2.25 (br-m, 1H), 2.21 (s, 6H), 2.17 (dd,J=12.3, 6.3 Hz, 1H), 1.42 (s, 9H);¹³C NMR (150 MHz, CDCI₃) δ155.87,138.10, 129.84, 128.39, 126.38, 79.30, 61.93, 49.49, 45.69, 39.02,28.54.

Benzyl (S)-(1-(dimethylamino)-3-phenylpropan-2-yl)carbamate (L10)

The corresponding diamine S3 was acylated with benzyl chloroformate (7.5mmol, 1.28 g) to provide L10 as colorless oil, which was used withoutfurther purification. ¹H NMR (600 MHz, CDCI₃) δ7.37-7.30 (m, 5H), 7.27(t, J=7.2 Hz, 2H), 7.21 (tt, J=7.5, 1.5 Hz, 2H), 7.16 (d, J=7.2 Hz, 2H),5.12 (d, J=12.0 Hz, 1H), 5.06 (d, J=12.0 Hz, 1H), 4.95 (br, 1H, N—H),3.94-3.92 (br-m, 1H), 2.99-2.96 (br-m, 1H), 2.84 (dd, J=13.8, 6.6 Hz,1H), 2.27 (dd, J=12.0, 9.0 Hz, 1H), 2.20-2.16 (m, 7H); ¹³C NMR (150 MHz,CDCI₃) δ156.33, 137.81, 136.84, 129.82, 128.63, 128.47, 128.16, 128.15,126.51, 66.64, 61.96, 50.10, 45.71, 38.99.

(S)-N-(1-(dimethylamino)-3-methylbutan-2-yl)acetamide (L11)

L11 was synthesized following the standard procedure as colorless oiland used without further purification ¹H NMR (600 MHz, CDCI₃) δ5.50(br-d, J=4.8 Hz, 1H, N—H), 3.96-3.91 (m, 1H), 2.35 (dd, J=12.0, 9.6 Hz,1H), 2.22 (s, 6H), 2.20 (dd, J=12.6, 5.4 Hz, 1H), 2.01 (s, 3H),1.98-1.93 (m, 1H), 0.90 (d, J=6.6 Hz, 3H), 0.88 (d, J=7.2 Hz, 3H); ¹³CNMR (150 MHz, CDCI₃) δ170.34, 60.15, 51.78, 45.86, 30.25, 23.78, 18.81,17.80.

N-((2S,3S)-1-(dimethylamino)-3-methylpentan-2-yl)acetamide (L12)

L12 was synthesized following the standard procedure as colorless oiland used without further purification. ¹H NMR (600 MHz, CDCI₃) δ5.57(br-d, J=6.0 Hz, 1H, N—H), 3.98-3.93 (m, 1H), 2.36 (dd, J=12.6, 4.2 Hz,1H), 2.20 (s, 6H), 2.16 (dd, J=12.3, 5.1 Hz, 1H), 2.00 (s, 3H),1.80-1.75 (m, 1H), 1.47-1.40 (m, 1H), 1.13-1.05(m, 1H), 0.92 (t, J=7.5Hz, 3H), 0.86 (d, J=6.6 Hz, 3H);¹³C NMR (150 MHz, CDCI₃) δ170.24, 59.17,51.21, 45.85, 36.95, 25.49, 23.82, 14.70, 12.17.

(S)-N-(1-(dimethylamino)-3,3-dimethylbutan-2-yl)acetamide (L13)

L13 was synthesized following the standard procedure as white solid andpurified by reverse phase column.¹H NMR (600 MHz, CDCI₃) δ5.321 (br-d,J=6.0 Hz, 1H, N—H), 3.94 (ddd, J=10.9, 9.8, 3.9 Hz, 1H), 2.32 (dd,J=12.3, 11.1 Hz, 1H), 2.25 (dd, J=12.3, 9.9 Hz, 1H), 2.20 (s, 6H), 2.02(s, 3H), 0.91 (s, 9H); ¹³C NMR (150 MHz, CDCI₃) δ170.42, 59.55, 54.41,45.87, 34.61, 26.64, 23.85.

(S)-N-(1-(dimethylamino)-4-methylpentan-2-yl)acetamide (L14)

L14 was synthesized following the standard procedure as white solid andpurified by reverse phase column. ¹H NMR (600 MHz, CDCI₃) δ5.50 (br-d,J=8.4 Hz, 1H, N—H), 4.10-4.04 (m, 1H), 2.33 (dd, J=12.3, 8,1 Hz, 1H),2.24 (s, 6H), 2.21 (dd, J=12.6, 6.0 Hz, 1H), 1.98 (s, 3H), 1.68-1.61 (m,1H), 1.39-1.31 (m, 2H), 0.93 (d, J=6.0 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H);¹³C NMR (150 MHz, CDCI₃) δ169.98, 63.86, 46.01, 45.89, 43.35, 25.02,23.73, 23.24, 22.52.

(S)-N-(2-(dimethylamino)-1-phenylethyl)acetamide (L15)

L15 was synthesized following the standard procedure as pale-yellowsolid and used without further purification. ¹H NMR (600 MHz, CDCI₃)δ7.32 (t, J=7.2 Hz, 2H), 7.28-7.26 (m, 2H), 7.24-7.22 (m, 1H), 6.24 (br,1H, N—H), 4.88 (dt, J=10.5, 5.4 Hz, 1H), 2.58 (dd, J=12.9, 9.9 Hz, 1H),2.41 (dd, J=12.6, 5.4 Hz, 1H), 2.24 (s, 6H), 2.04 (s, 3H);¹³C NMR (150MHz, CDCI₃) δ170.17, 141.54, 128.67, 127.35, 126.29, 64.80, 51.92,45.56, 23.55.

(S)-N-(1-(dimethylamino)-4-phenylbutan-2-yl)acetamide (L16)

L16 was synthesized following the standard procedure as colorless oiland used without further purification. ¹H NMR (600 MHz, CDCI₃) δ7.27 (t,J=7.5 Hz, 2H), 7.20-7.16 (m, 3H), 5.54 (br-d, J=6.6 Hz, 1H, N—H),4.06-4.00 (m, 1H), 2.68-2.65 (m, 2H), 2.38 (dd, J=12.3, 8.7 Hz, 1H),2.24 (dd, J=12.3, 5.7 Hz, 1H), 2.21 (s, 6H), 1.97 (s, 3H), 1.93-1.88 (m,1H), 1.81-1.75 (m, 1H);¹³C NMR (150 MHz, CDCI₃) δ170.23, 142.08, 128.52,128.48, 125.99, 63.10, 47.71, 46.00, 35.46, 32.27, 23.73.

(S)-N-(1-(dimethylamino)-3-(4-methoxyphenyl)propan-2-yl)acetamide (L17)

L17 was synthesized following the standard procedure as pale-yellowsolid and used without further purification. ¹H NMR (600 MHz, CDCI₃)δ7.10-7.08 (m, 2H), 6.84-6.82 (m, 2H), 5.55 (br-d, J=7.2 Hz, 1H, N—H),4.17-4.11 (m, 1H), 3.79 (s, 3H), 2.90 (dd, J=13.8, 4.8 Hz, 1H), 2.79(dd, J=13.8, 6.6 Hz, 1H), 2.27 (dd, J=12.3, 9.3 Hz, 1H), 2.19 (s, 6H),2.15 (dd, J=12.3, 5.7 Hz, 1H), 1.96(s, 3H);¹³C NMR (150 MHz, CDCI₃)δ170.22, 158.33, 130.78, 129.78, 113.85, 61.52, 55.35, 48.35, 45.71,37.59, 23.74.

(S)-N-(1-(2,6-difluorophenyl)-3-(dimethylamino)propan-2-yl)acetamide(L18)

L18 was synthesized following the standard procedure as pale-yellowsolid and used without further purification.¹H NMR (600 MHz, CDCI₃)δ7.19-7.14 (m, 1H), 6.88-6.84 (m, 2H), 5.60 (br-d, J=7.8 Hz, 1H, N—H),4.29-4.23 (m, 1H), 3.08 (dd, J=13.8, 5.4 Hz, 1H), 2.81 (dd, J=13.8, 7.8Hz, 1H), 2.40 (dd, J=12.3, 8.7 Hz, 1H), 2.27-2.23 (m, 7H), 1.90 (s,3H);¹³C NMR (150 MHz, CDCI₃) δ170.24, 161.94 (dd, J=245, 8 Hz), 128.32(t, J=10 Hz), 114.14 (t, J=20 Hz), 111.16 (dd, J=20, 4.5 Hz), 62.50,47.68, 46.78, 26.02, 23.51;¹⁹F NMR (376 MHz, CDCI₃) δ-114.52 (s, 2F);

(S)-N-(1-([1,1′:3′,1″-terphenyl]-2′-yl)-3-(dimethylamino)propan-2-yl)acetamide(L19)

L19 was synthesized following the standard procedure, and could bepurified by recrystallized to provide white solid.¹H NMR (600 MHz,CDCI₃) δ7.46-7.41 (m, 8H), 7.38-7.35 (m, 2H), 7.29-7.27 (m, 1H), 7.18(d, J=7.8 Hz, 2H), 4.60 (br-d, J=9.6 Hz, 1H), 3.77-2.70 (m, 1H), 3.12(d, J=13.8, 4.2 Hz, 1H), 2.80 (d, J=14.4, 10.8 Hz, 1H), 1.85 (dd,J=12.0, 6.6 Hz, 1H), 1.72 (s, 6H), 1.69 (s, 3H), 1.61 (dd, J=12.0, 7.8Hz, 1H); ¹³C NMR (150 MHz, CDCI₃) δ169.16, 143.49, 142.56, 133.60,129.92, 129.75, 128.52, 127.18, 126.19, 64.15, 48.22, 45.36, 32.54,23.57.

(S)-N-(1-(dimethylamino)-3-(naphthalen-2-yl)propan-2-yl)acetamide (L20)

L20 was synthesized following the standard procedure as pale-yellowsolid and used without further purification.¹H NMR (600 MHz, CDCI₃)δ7.82-7.87 (m, 3H),7.62 (s, 1H), 7.47-7.42 (m, 2H), 7.35 (dd, J=8.4, 1.2Hz, 1H), 5.64 (br-d, J=6.0 Hz, 1H, N—H), 4.30-4.24 (m, 1H), 3.17 (dd,J=13.8, 4.8 Hz, 1H), 2.98 (dd, J=13.8, 6.6 Hz, 1H), 2.33 (dd, J=12.3,9.3 Hz, 1H), 2.21-2.18 (m, 7H), 1.97 (s, 3H); ¹³C NMR (151 MHz, CDCI₃)δ170.35, 135.50, 133.57, 132.35, 128.29, 128.20, 127.99, 127.76, 127.65,126.15, 125.58, 61.54, 48.43, 45.68, 38.77, 23.74.

(S)-N-(1-(dimethylamino)-3-(naphthalen-1-yl)propan-2-yl)acetamide (L21)

L21 was synthesized following the standard procedure as pale-yellowsolid and used without further purification.¹H NMR (600 MHz, CDCI₃)δ8.45 (d, J=8.4 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H),7.56 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.50-7.46 (m, 1H), 7.38 (dd, J=8.1,6.9 Hz, 1H), 7.29 (d, J=6.6 Hz, 1H), 5.82 (br-d, J=6.0 Hz, 1H),4.31-4.26 (m, 1H), 3.74 (dd, J=13.9, 4.8 Hz, 1H), 3.04 (dd, J=13.8, 8.4Hz, 1H), 2.40 (dd, J=12.3, 9.3 Hz, 1H), 2.17-2.14 (m, 7H), 1.98 (s, 3H);¹³C NMR (150 MHz, CDCI₃) δ170.73, 134.43, 134.02, 132.73, 128.64,127.87, 127.43, 126.32, 125.83, 125.28, 124.88, 61.79, 48.14, 45.60,36.55, 23.74.

Preparation of Substrates

1, 4a, and 4b were purchased from commercial sources. 4c and 4d weresynthesized from the reported procedure.⁵

To a flask charged with a magnetic stir bar and the arylacetonitrile(S5) (6.6 mmol) was added 1-bromo-2-chloroethane (9.9 mmol),benzyltriethylammonium chloride (0.132 mmol), and 50% aqueous sodiumhydroxide (39.6 mmol). The resulting solution was stirred at 50° C.under a reflux condenser and ambient atmosphere for 12 h. The solutionwas poured into water and extracted with dichloromethane twice. Thecombined organic extracts were washed with 3 N HCl, saturated aqueousNaHCO₃, and brine. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give the desired1-aryl-1-cyanocyclopropane product (S6), typically in sufficient purityto be carried forward without further purification to the next step.

To a flask containing 1-aryl-1-cyanocyclopropane (S6) (6.6 mmol) wasadded a slurry of lithium hydroxide in water (4.0 M, 212 mmol). Theflask was heated to reflux and stirred for 24 h. The reaction was cooledto room temperature, then 2 N HCl was added until pH<1. The solution wasextracted with ethyl acetate for three times. The combined ethyl acetateextracts were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to give the desired 1-arylcyclopropanecarboxylic acid product,typically in sufficient purity to be carried forward to Pd-catalyzedreaction without further purification. The spectra of 4c⁶ and 4d⁷ havebeen reported in the literature.

4e-4j were synthesized following the previously reported procedure.⁵

A freshly prepared solution of lithium diispropylamide (12 mmol) inTHF/hexanes (30 ml) was cooled to −78° C. A solution of tent-butylcyclopropanecarboxylate (S7) (10 mmol, 1.42 g) in THF (10 ml) was addedslowly dropwise over 5 min. The resulting solution was stirred at −78°C. for 2 h. A solution of the alkyl bromide (30 mmol) in THF (10 ml) wasadded slowly dropwise over 10 min. The solution was then allowed to warmto room temperature slowly and stirred overnight. Then, the reaction wasquenched by addition of saturated aqueous ammonium chloride. The aqueousphase was extracted twice with diethyl ether. The combined organicphases were washed with brine, dried over sodium sulfate, filtered andconcentrated in vacuo. The product (S8) was then purified by silica gelflash chromatography (typically 3% v/v ether in hexanes).

10 ml of 4 N HCl in dioxane was added to the previously preparedtert-butyl ester, and 0.5 ml of water was added to the solution(warning: exothermic process). The mixture was stirred at roomtemperature for 24 h. The reaction solution was concentrated in vacuo,and then the residue was dissolved in methanol. The resulting solutionwas dried over sodium sulfate, filtered and concentrated to give thedesired free acid, typically in sufficient purity to be carried forwardto Pd-catalyzed reaction without further purification. The spectra of4e⁸ and 4i⁹ have been reported.

1-Butylcyclopropane-1-carboxylic acid (4f)

¹H NMR (600 MHz, CDCI₃) δ1.52-1.49 (m, 2H), 1.47-1.42 (m, 2H), 1.30 (q,J=7.4 Hz, 2H), 1.27-1.25 (m, 2H), 0.89 (t, J=7.2, 3H), 0.76-0.74 (m,2H); ¹³C NMR (150 MHz, CDCI₃) δ182.13, 33.46, 29.88, 23.44, 23.02,16.59, 14.16.

1-(3-Phenylpropyl)cyclopropane-1-carboxylic acid (4g)

¹H NMR (600 MHz, CDCI₃) δ7.28-7.25 (m, 2H), 7.18-7.16 (m, 3H), 2.61 (t,J=7.8 Hz, 2H), 1.84-1.78 (m, 2H), 1.57-1.54 (m, 2H), 1.27-1.26 (m, 2H),0.74-0.73 (m. 2H); ¹³C NMR (150 MHz, CDCI₃) δ182.57, 142.46, 128.49,128.42, 125.84, 36.12, 33.41, 29.34, 28.22, 23.41, 16.70.

1-(5-Chloropentyl)cyclopropane-1-carboxylic acid (4h)

¹H NMR (600 MHz, CDCI₃) δ3.53 (t, J=6.6 Hz, 2H), 1.78 (p, J=7.2 Hz, 2H),1.53-1.49 (m, 4H), 1.45-1.40 (m, 2H), 1.29-1.27 (m, 2H), 0.77-0.75 (m,2H); ¹³C NMR (150 MHz, CDCI₃) δ182.27, 45.20, 33.61, 32.63, 27.13,26.98, 23.38, 16.69.

1-(4-Fluorobenzyl)cyclopropane-1-carboxylic acid (4j)

¹H NMR (600 MHz, CDCI₃) δ7.21-7.18 (m, 2H), 6.97-6.93 (m, 2H), 2.92 (s,2H), 1.36-1.35 (m, 2H), 0.88-0.86 (m, 2H); ¹³C NMR (150 MHz, CDCI₃)δ181.94, 161.69 (d, J=243 Hz), 134.99 (d, J=3 Hz), 130.70 (d, J=8 Hz),115.08 (d, J=21 Hz), 37.26, 23.89, 16.22; ¹⁹F NMR (376 MHz, CDCI₃)δ-117.33 (s, 1F).

To a stirred suspension of 60% sodium hydride (NaH) in mineral oil(0.120 g, 30.0 mmol) in anhydrous THF (10 mL), cooled in an ice bath,was added methyl 1-hydroxymethyl cyclopropanecarboxylic acid (10.0 mmol,1.30 g). The resultant suspension was stirred for 20 min at roomtemperature. Benzyl bromide (10.0 mmol, 1.71 g, 1.21 ml) was slowlyadded at 0° C., and the reaction was stirred at room temperatureovernight. The reaction suspension was chilled in an ice bath, and theexcess NaH was quenched with water (15 mL). The reaction mixture wasextracted with ethyl acetate (3×25 mL). The combined organics were driedover MgSO₄, filtered, and concentrated. The residue was purified byflash chromatography (silica gel, 10% ethyl acetate in hexanes) todeliver S10.

S10 was dissolved in the mixture of THF (32 ml), water (32 ml) and MeOH(16 ml) and then LiOH·H₂O (30 mmol, 0.126 g) was added. The resultingmixture was stirred overnight and then was acidified by adding 3 M HClsolution. The mixture was extracted with ethyl acetate. Then combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo to provide 4k which was directly used in the Pd-catalyzed reactionwithout further purification.

1-((Benzyloxy)methyl)cyclopropane-1-carboxylic acid (4k)

¹H NMR (600 MHz, CDCI₃) δ7.37-7.32 (m, 4H), 7.31-7.28 (m, 1H), 4.59 (s,2H), 3.61 (s, 2H), 1.36-1.34 (m, 2H), 0.94-0.93 (m, 2H); ¹³C NMR (150MHz, CDCI₃) δ178.28, 137.83, 128.63, 127.99, 127.91, 73.35, 71.80,23.55, 14.66.

Diethyl azodicarboxylate (7.50 mmol) was added to a cooled (0° C.)solution of methyl 1-hydroxymethyl cyclopropanecarboxylate (651 mg, 5.00mmol), triphenylphosphine (1.97 g, 7.50 mmol) and phthalimide (1.103 g,7.50 mmol) in THF (12 mL). After being stirred at room temperature for12 h, the reaction mixture was concentrated under vacuum and purified bycolumn chromatography on silica gel (eluent: EtOAc/hexanes=1:5) to giveS11.

NaOH (6.00 mmol, 0.240 g) was added to a cooled (0° C.) solution of S11(3.00 mmol) in dioxane (6 mL) and H₂O (3 mL). The reaction mixture wasstirred for 3 h at room temperature, then poured into 2 N HCl (5 mL) andextracted with EtOAc. The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was heated to 150° C. for 1 h and then cooled to roomtemperature. The solid was purified by flash chromatography (eluent:EtOAc/hexanes=1:1 with 1% v/v HOAc) to give 4l as white solid.

1-((1,3-Dioxoisoindolin-2-yl)methyl)cyclopropane-1-carboxylic acid (4l)

¹H NMR (600 MHz, CDCI₃) δ7.86-7.83 (m, 2H), 7.74-7.70 (m, 2H), 4.01 (s,2H), 1.38-1.36 (m, 2H), 1.23-1.10 (m, 2H); ¹³C NMR (151 MHz, CDCI₃)δ179.98, 168.44, 134.17, 132.04, 123.52, 39.98, 22.48, 15.76.

6¹⁰ and 8¹¹ were synthesized following the reported procedures.

Enantioselective Arylation of Cyclopropanecarboxylic Acid

General procedure for enantioselective arylation ofcyclopropanecarboxylic acid: A 2-dram vial equipped with a magnetic stirbar was charged with Pd(OAc)2 (4.4 mg, 10 mol %) and L1 (8.8 mg, 20 mol%) in HFIP (0.25 ml). The appropriate cyclopropanecarboxylic acidsubstrate (0.20 mmol), Ag₂CO₃ (82.7 mg, 0.30 mmol), Na₂CO₃ (31.8 mg,0.30 mmol) and aryl iodide (0.40 mmol) was then added. Subsequently, thevial was capped and closed tightly. The reaction mixture was thenstirred at the rate of 200 rpm at 80° C. for 16 h. After being allowedto cool to room temperature, the mixture was diluted with ethyl acetate,and 0.1 ml of acetic acid was then added. The mixture was passed througha pad of Celite with ethyl acetate as the eluent to remove any insolubleprecipitate. The resulting solution was concentrated, and the residualmixture was dissolved with a minimal amount of acetone and loaded onto apreparative TLC plate. The pure product was then isolated usingpreparative TLC with ethyl acetate and hexanes (1/4 to 1/1) as theeluent and 1% v/v of acetic acid as the additive.

(1R,2S)-2-(4-(methoxycarbonyl)phenyl)cyclopropane-1-carboxylic acid (3a)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=2/1 with 1% v/v of acetic acid). Theproduct was obtained as a white solid (80% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IA-3 column, 15% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 1.734 min (major) and 2.616 min (minor), 97:3er);

¹H NMR (600 MHz, CDCI₃) δ7.92 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H),3.91 (s, 3H), 2.63 (q, J=8.6 Hz, 1H), 2.08 (ddd, J=9.2, 7.9, 5.7 Hz,1H), 1.69 (dt, J=7.5, 5.4 Hz, 1H), 1.42 (td, J=8.2, 5.2 Hz, 1H); ¹³C NMR(150 MHz, CDCI₃) δ176.27, 167.21, 141.51, 129.46, 129.39, 128.74, 52.18,26.48, 21.81, 12.40;

HRMS (ESI-TOF) m/z Calcd for C₁₂H₁₃O₄ ⁺ [M+H]⁺ 221.0808, found 221.0814;

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

3a could also be obtained following standard condition except usingcyclopropanecarboxylic acid (0.40 mmol), aryl iodide (0.20 mmol) andAg₂CO₃ (0.20 mmol) as a white solid in the yield of 85% with 96:4 er.

(1R,2S)-2-(4-acetylphenyl)cyclopropane-1-carboxylic acid (3b)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=2/1 with 1% v/v of acetic acid). Theproduct was obtained as a white solid (83% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IG-3 column, 25% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 1.922 min (minor) and 2.268 min (major), 96:4er);

¹H NMR (600 MHz, CDCI₃) δ7.84 (d, J=8.4 Hz, 2H), 7.32 (d, J=7.8 Hz, 2H),2.64 (q, J=8.6 Hz, 1H), 2.58 (s, 3H), 2.10 (ddd, J=9.1, 7.9, 5.7 Hz,1H), 1.71 (dt, J=7.7, 5.4 Hz, 1H), 1.44 (td, J=8.2, 5.2 Hz, 1H); ¹³C NMR(150 MHz, CDCI₃) δ198.11, 176.15, 141.79, 135.82, 129.63, 128.20, 26.74,26.48, 21.86, 12.45;

HRMS (ESI-TOF) m/z Calcd for C₁₂H₁₃O₃ ⁺ [M+H]⁺ 205.0859, found 205.0857;

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-(4-nitrophenyl)cyclopropane-1-carboxylic acid (3c)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=1/1 with 1% v/v of acetic acid). Theproduct was obtained as a pale-yellow solid (53% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IG-3 column, 10% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 4.443 min (minor) and 4.907 min (major), 90:10er);

¹H NMR (600 MHz, CDCI₃) δ8.11 (d, J=9.0 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H),2.67 (q, J=8.5 Hz, 1H), 2.15 (ddd, J=9.0, 8.1, 5.7 Hz, 1H), 1.72 (dt,J=7.6, 5.5 Hz, 1H), 1.50 (td, J=8.2, 5.3 Hz, 1H); ¹³C NMR (150 MHz,CDCI₃) δ176.03, 147.00, 143.86, 130.30, 123.29, 26.21, 22.06, 12.73.

HRMS (ESI-TOF) m/z Calcd for C₁₀H₁₀NO₄ ⁺ [M+H]⁺ 208.0604, found208.0607.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylic acid (3d)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=4/1 with 1% v/v of acetic acid). Theproduct was obtained as a pale-yellow oil (86% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® AS-3 column, 5% ^(i)PrOH/CO₂, flow rate 1.0 mL/min,retention time 5.853 min (major) and 6.402 min (minor), 97:3 er);

¹H NMR (600 MHz, CDCI₃) δ7.49 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H),2.64 (q, J=8.6 Hz, 1H), 2.09 (ddd, J=9.2, 7.8, 5.6 Hz, 1H), 1.69 (dt,J=7.7, 5.4 Hz, 1H), 1.50 (ddd, J=8.6, 7.8, 5.3 Hz, 1H); ¹³C NMR (150MHz, CDCI₃) δ176.59, 140.17, 129.75, 129.12 (q, J=32 Hz), 124.98 (q, J=4Hz), 124.38 (q, J=270 Hz), 26.25, 21.74, 12.32; ¹⁹F NMR (376 MHz, CDCI₃)δ-62.70 (s, 3F);

HRMS (ESI-TOF) m/z Calcd for C₁₁H₁₀F₃O₂ ⁺ [M+H]⁺ 231.0627, found231.0631.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-(4-cyanophenyl)cyclopropane-1-carboxylic acid (3e)

Substrate 1 was arylated following the general arylation procedureexcept using AgOAc (3.0 equiv) and NaHCO₃ (1.5 equiv) instead of Ag₂CO₃and Na₂CO₃. (eluent: hexanes/ethyl acetate=1/1 with 1% v/v of aceticacid). The product was obtained as a pale-yellow solid (53% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IG-3 column, 15% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 1.940 min (minor) and 2.366 min (major), 96:4er);

¹H NMR (600 MHz, CDCI₃) δ7.54(d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H),2.64 (q, J=8.6 Hz, 1H), 2.12 (ddd, J=9.2, 7.9, 5.7 Hz, 1H), 1.69 (dt,J=7.7, 5.5 Hz, 1H), 1.50 (td, J=8.2, 5.3 Hz, 1H); ¹³C NMR (150 MHz,CDCI₃) δ176.38, 141.71, 131.84, 130.22, 119.06, 110.68, 26.44, 21.98,12.43;

HRMS (ESI-TOF) m/z Calcd for C₁₁H₁₀NO₂ ⁺ [M+H]⁺ 188.0706, found188.0704.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-(4-fluorophenyl)cyclopropane-1-carboxylic acid (3f)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=4/1 with 1% v/v of acetic acid). Theproduct was obtained as a pale-yellow solid (73% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IG-3 column, 7% (^(i)PrOH containing 0.5% HCO₂H)/CO₂, flowrate 4 mL/min, retention time 2.492 min (major) and 3.108 min (minor),96:4 er);

¹H NMR (600 MHz, CDCI₃) δ7.19 (dd, J=8.4, 5.4 Hz, 2H), 7.32 (t, J=8.7Hz, 2H), 2.59 (q, J=8.5 Hz, 1H), 2.09 (td, J=8.4, 6.2 Hz, 1H), 1.69 (dt,J=7.8, 5.4 Hz, 1H), 1.50 (ddd, J=8.6, 8.0, 5.1 Hz, 1H); ¹³C NMR (150MHz, CDCI₃) δ176.27, 161.90 (d, J=243 Hz), 131.71 (d, J=3 Hz), 130.90(d, J=8 Hz), 114.95 (d, J=21 Hz), 25.87, 21.38, 12.33; ¹⁹F NMR (376 MHz,CDCI₃) δ-116.17 (s, 1F);

HRMS (ESI-TOF) m/z Calcd for C₁₀H₁₀FO₂ ⁺ [M+H]⁺ 181.0659, found181.0658.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-(4-chlorophenyl)cyclopropane-1-carboxylic acid (3g)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=4/1 with 1% v/v of acetic acid). Theproduct was obtained as a pale-yellow solid (70% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IA-3 column, 5% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 3.060 min (major) and 3.580 min (minor), 96:4er);

¹H NMR (600 MHz, CDCI₃) δ7.22 (d, J=8.4, 2H), 7.32 (d, J=8.4 Hz, 2H),2.58 (q, J=8.6 Hz, 1H), 2.06 (ddd, J=8.2, 7.3, 5.1 Hz, 1H), 1.64 (dt,J=7.7, 5.4 Hz, 1H), 1.39 (ddd, J=8.6, 7.8, 5.1 Hz, 1H); ¹³C NMR (150MHz, CDCI₃) δ175.98, 134.56, 132.72, 130.75, 128.26, 25.98, 21.50,12.31;

HRMS (ESI-TOF) m/z Calcd for C₁₀H₁₀ClO₂ ⁺ [M+H]⁺ 197.0364, found197.0362.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-(4-bromophenyl)cyclopropane-1-carboxylic acid (3h)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=4/1 with 1% v/v of acetic acid). Theproduct was obtained as a pale-yellow solid (81% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IG-3 column, 15% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 2.068 min (minor) and 2.276 min (major), 94:6er);

¹H NMR (600 MHz, CDCI₃) δ7.37 (d, J=8.4, 2H), 7.10 (d, J=8.4 Hz, 2H),2.55 (q, J=8.6 Hz, 1H), 2.04 (ddd, J=9.2, 7.8, 5.6 Hz, 1H), 1.63 (dt,J=7.7, 5.4 Hz, 1H), 1.38 (td, J=8.2, 5.2 Hz, 1H); ¹³C NMR (150 MHz,CDCI₃) δ176.92, 135.08, 131.17, 131.13, 120.82, 26.07, 21.63, 12.27;

HRMS (ESI-TOF) m/z Calcd for C₁₀H₁₀BrO₂ ⁺ [M+H]⁺ 240.9859, found240.9856.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-(p-tolyl)cyclopropane-1-carboxylic acid (3i)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=4/1 with 1% v/v of acetic acid). Theproduct was obtained as a pale-yellow solid (73% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IA-3 column, 7% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 1.938 min (major) and 2.725 min (minor), 98:2er);

¹H NMR (600 MHz, CDCI₃) δ7.13 (d, J=7.8, 2H), 7.05 (d, J=7.8 Hz, 2H),2.59 (q, J=8.6 Hz, 1H), 2.30 (s, 3H), 2.05-2.01 (m, 1H), 1.65-1.62 (m,1H), 1.35 (td, J=8.1, 5.1 Hz, 1H); ¹³C NMR (150 MHz, CDCI₃) δ175.74,136.44, 133.01, 129.25, 128.85, 26.33, 21.39, 21.25, 12.23; HRMS(ESI-TOF) m/z Calcd for C₁₁H₁₃O₂ ⁺ [M+H]⁺ 177.0910, found 177.0905.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-(4-((diethoxyphosphoryl)methyl)phenyl)cyclopropane-1-carboxylicacid (3j)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=1/1 with 1% v/v of acetic acid). Theproduct was obtained as a pale-yellow oil (74% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IG-3 column, 20% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 1.761 min (minor) and 2.047 min (major), 96:4er);

¹H NMR (600 MHz, CDCI₃) δ7.20 (d, J=7.8, 2H), 7.00 (dd, J=8.1, 2.4 Hz,2H), 4.03-3.85 (m, 4H), 2.79 (d, J=14.4 Hz, 2H), 2.57 (q, J=9.1 Hz, 1H),2.10 (ddd, J=9.3, 7.7, 5.7 Hz, 1H), 1.67 (dt, J=7.5, 5.4 Hz, 1H), 1.31(td, J=8.3, 5.1 Hz, 1H), 1.19 (t, J=7.1 Hz, 3H), 1.16 (t, J=7.1 Hz, 3H);¹³C NMR (150 MHz, CDCI₃) δ174.19, 135.19 (d, J=4 Hz), 129.71 (d, J=10Hz), 129.61 (d, J=3 Hz), 129.39 (d, J=6 Hz), 62.67 (d, J=7 Hz), 62.54(d, J=7 Hz), 32.82 (d, J=136 Hz), 25.57, 21.85, 16.39 (d, J=6 Hz), 16.35(d, J=6 Hz), 11.26; HRMS (ESI-TOF) m/z Calcd for C₁₅H₂₁O₅P⁺ [M+H]⁺313.1199, found 313.1203.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropane-1-carboxylic acid(3k)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=4/1 with 1% v/v of acetic acid). Theproduct was obtained as a pale-yellow oil (75% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IA-3 column, 3% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 2.163 min (major) and 2.503 min (minor), 97:3er);

¹H NMR (600 MHz, CDCI₃) δ7.23 (d, J=8.4, 2H), 7.08 (d, J=7.8 Hz, 2H),2.59 (q, J=8.6 Hz, 1H), 2.04 (ddd, J=9.1, 7.8, 5.6 Hz, 1H), 1.63 (dt,J=7.7, 5.4 Hz, 1H), 1.39 (td, J=8.5, 5.2 Hz, 1H); ¹³C NMR (150 MHz,CDCI₃) δ177.06, 148.14 (q, J=2 Hz), 134.83, 130.74, 120.63 (q, J=255Hz), 120.53, 25.88, 21.60, 12.30; ¹⁹F NMR (376 MHz, CDCI₃) δ-58.12 (s,3F); 11.26;

HRMS (ESI-TOF) m/z Calcd for C₁₁H₁₀F₃O₃ ⁺ [M+H]⁺ 247.0577, found247.0579.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-(3-(methoxycarbonyl)phenyl)cyclopropane-1-carboxylic acid (3l)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=2/1 with 1% v/v of acetic acid). Theproduct was obtained as a white solid (76% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IG-3 column, 10% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 3.003 min (minor) and 3.428 min (major), 96:4er);

¹H NMR (600 MHz, CDCI₃) δ7.93 (s, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.40 (d,J=7.2 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 3.91 (s, 3H), 2.64 (q, J=8.5 Hz,1H), 2.08-2.05 (m, 1H), 1.70 (dt, J=7.5, 5.4 Hz, 1H), 1.41 (td, J=8.2,5.2 Hz, 1H); ¹³C NMR (150 MHz, CDCI₃) δ175.99, 167.22, 136.49, 133.86,130.78, 130.03, 128.25, 128.13, 52.24, 26.27, 21.44, 12.31;

HRMS (ESI-TOF) m/z Calcd for C₁₂H₁₃O₄ ⁺ [M+H]⁺ 221.0808, found 221.0807.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-(3-formylphenyl)cyclopropane-1-carboxylic acid (3m)

Substrate 1 was arylated following the general arylation procedureexcept using AgOAc (3.0 equiv) and NaHCO₃ (1.5 equiv) instead of Ag₂CO₃and Na₂CO₃. (eluent: hexanes/ethyl acetate=2/1 with 1% v/v of aceticacid). The product was obtained as a pale-yellow oil (70% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IG-3 column, 20% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 1.819 min (minor) and 2.479 min (major), 93:7er);

¹H NMR (600 MHz, d⁶-acetone) δ10.02 (s, 1H), 7.84 (s, 1H), 7.74 (d,J=7.8 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 2.74 (q,J=8.5 Hz, 1H), 2.21-2.17 (m, 1H), 1.67 (dt, J=7.4, 5.3 Hz, 1H), 1.44(td, J=8.2, 4.9 Hz, 1H); ¹³C NMR (150 MHz, d⁶-acetone) 193.04, 171.84,139.29, 137.37, 136.19, 131.16, 129.37, 128.42, 25.53, 22.27, 11.76;

HRMS (ESI-TOF) m/z Calcd for C₁₁H₁₁O₃ ⁺ [M+H]⁺ 191.0703, found 191.0700.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylic acid (3n)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=4/1 with 1% v/v of acetic acid). Theproduct was obtained as a pale-yellow oil (84% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IG-3 column, 3% (^(i)PrOH containing 0.5% HCO₂H)/CO₂, flowrate 4 mL/min, retention time 3.999 min (major) and 4.584 min (minor),96:4 er);

¹H NMR (600 MHz, CDCI₃) δ7.48 (s, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.39 (d,J=7.8 Hz, 1H), 7.34 (t, J=7.8 Hz, 1H), 2.64 (q, J=8.5 Hz, 1H), 2.08(ddd, J=9.1, 7.8, 5.6 Hz, 1H), 1.68 (dt, J=7.7, 5.4 Hz, 1H), 1.43 (ddd,J=8.6, 7.9, 5.2 Hz, 1H); ¹³C NMR (150 MHz, CDCI₃) δ176.64, 137.05,132.74, 130.42 (q, J=32 Hz), 128.45, 126.27 (q, J=4 Hz), 124.27 (q,J=270 Hz), 123.76 (q, J=4 Hz), 26.23, 21.60, 12.37; ¹⁹F NMR (376 MHz,CDCI₃) δ-62.89 (s, 3F);

HRMS (ESI-TOF) m/z Calcd for C₁₁H₁₀F₃O₂ ⁺ [M+H]⁺ 231.0627, found231.0628.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-(3-fluorophenyl)cyclopropane-1-carboxylic acid (3o)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=4/1 with 1% v/v of acetic acid). Theproduct was obtained as a pale-yellow oil (79% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IA-3 column, 2% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 4.482 min (major) and 5.337 min (minor), 97:3er);

¹H NMR (600 MHz, CDCI₃) δ7.20 (td, J=7.9, 6.1 Hz, 1H), 7.01 (dt, J=7.8,0.8 Hz, 1H), 6.93 (d, J=10.2 Hz, 1H), 6.89 (td, J=8.4, 2.5 Hz, 1H), 2.60(q, J=8.6 Hz, 1H), 2.05 (ddd, J=9.2, 7.8, 5.6 Hz, 1H), 1.64 (dt, J=7.7,5.4 Hz, 2H), 1.38 (ddd, J=8.6, 7.8, 5.1 Hz, 1H); ¹³C NMR (150 MHz,CDCI₃) δ176.56, 162.64 (d, J=245 Hz), 138.66 (d, J=8 Hz), 129.47 (d, J=9Hz), 125.14 (d, J=2 Hz), 116.30 (d, J=21 Hz), 113.92 (d, J=21 Hz),26.22, 21.57, 12.31; ¹⁹F NMR (376 MHz, CDCI₃) δ-114.29 (s, 1F);

HRMS (ESI-TOF) m/z Calcd for C₁₀H₁₀FO₂ ⁺ [M+H]⁺ 181.0659, found181.0658.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-(3-chlorophenyl)cyclopropane-1-carboxylic acid (3p)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=4/1 with 1% v/v of acetic acid). Theproduct was obtained as a pale-yellow oil (80% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IA-3 column, 3% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 4.252 min (major) and 5.031 min (minor), 96:4er);

¹H NMR (600 MHz, CDCI₃) δ7.24 (s, 1H), 7.19-7.15 (m, 2H), 7.11-7.09 (m,1H), 2.58 (q, J=8.6 Hz, 1H), 2.05 (ddd, J=9.2, 7.8, 5.6 Hz, 1H), 1.64(dt, J=7.7, 5.4 Hz, 1H), 1.38 (ddd, J=8.6, 7.8, 5.2 Hz, 1H); ¹³C NMR(150 MHz, CDCI₃) δ176.48, 138.14, 133.88, 129.65, 129.29, 127.58,127.19, 26.17, 21.51, 12.29;

HRMS (ESI-TOF) m/z Calcd for C₁₀H₁₀ClO₂ ⁺ [M+H]⁺ 197.0364, found197.0361.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-(m-tolyl)cyclopropane-1-carboxylic acid (3q)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=4/1 with 1% v/v of acetic acid). Theproduct was obtained as a pale-yellow oil (71% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IA-3 column, 5% MeOH/CO₂, flow rate 4 mL/min, retention time2.136 min (major) and 2.547 min (minor), 97:3 er);

¹H NMR (600 MHz, CDCI₃) δ7.13 (t, J=7.8 Hz, 1H), 7.06 (s, 1H), 7.03 (d,J=7.8 Hz, 1H), 7.01 (d, J=7.8 Hz, 1H), 2.59 (q, J=8.6 Hz, 1H), 2.33 (s,3H), 2.01 (ddd, J=9.2, 7.8, 5.6 Hz, 1H), 1.65 (dt, J=7.7, 5.3 Hz, 1H),1.35 (td, J=8.2, 5.0 Hz, 1H); ¹³C NMR (150 MHz, CDCI₃) δ176.10, 137.61,135.95, 130.22, 127.97, 127.73, 126.35, 26.62, 21.49, 21.35, 12.18;

HRMS (ESI-TOF) m/z Calcd for C₁₁H₁₃O₂ ⁺ [M+H]⁺ 177.0910, found 177.0905.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-(3-methoxyphenyl)cyclopropane-1-carboxylic acid (3r)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=4/1 with 1% v/v of acetic acid). Theproduct was obtained as a pale-yellow oil (70% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IA-3 column, 10% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 1.670 min (major) and 2.114 min (minor), 97:3er);

¹H NMR (600 MHz, CDCI₃) δ7.15 (t, J=7.8 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H),6.78 (s, 1H), 6.74 (dd, J=8.4, 3.2 Hz, 1H), 3.76 (s, 3H), 2.59 (q, J=8.7Hz, 1H), 2.02 (ddd, J=9.3, 7.7, 5.6 Hz, 1H), 1.63 (dt, J=7.7, 5.3 Hz,1H), 1.35 (td, J=8.2, 5.0 Hz, 1H); ¹³C NMR (150 MHz, CDCI₃) δ177.04,159.37, 137.72, 129.05, 121.83, 114.90, 112.66, 55.26, 26.71, 21.56,12.35;

HRMS (ESI-TOF) m/z Calcd for C₁₁H₁₃O₃ ⁺ [M+H]⁺ 193.0859, found 193.0861.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-phenylcyclopropane-1-carboxylic acid (3s)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=4/1 with 1% v/v of acetic acid). Theproduct was obtained as a pale-yellow oil (70% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IA-3 column, 10% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 1.492 min (major) and 1.730 min (minor), 95:5er);

¹H NMR (600 MHz, CDCI₃) δ7.25-7.22 (m, 3H), 7.21-7.18 (m, 1H), 2.62 (q,J=8.7 Hz, 1H), 2.04 (ddd, J=9.0, 7.9, 5.7 Hz, 1H), 1.66 (dt, J=7.7, 5.3Hz, 1H), 1.37 (td, J=8.2, 5.1 Hz, 1H); ¹³C NMR (150 MHz, CDCI₃) δ176.20,136.07, 129.40, 128.10, 126.92, 26.64, 21.42, 12.16;

HRMS (ESI-TOF) m/z Calcd for C₁₀H₁₁O₂ ⁺ [M+H]⁺ 163.0754, found 163.0752.

The absolute stereochemistry was assigned based on known opticalrotation.¹² [α]²³ _(D)=−23.1° (c=1, CHCl₃), lit.[α]²³ _(D)=−27.6°(c=1.00, CHCl₃)

(1R,2S)-2-(2-(methoxycarbonyl)phenyl)cyclopropane-1-carboxylic acid (3t)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=2/1 with 1% v/v of acetic acid). Theproduct was obtained as a white solid (84% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IG-3 column, 15% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 1.947 min (minor) and 2.349 min (major), 98:2er);

¹H NMR (600 MHz, CDCI₃) δ7.84 (d, J=7.8 Hz, 1H), 7.42 (td, J=8.0, 1.2Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.28 (t, J=8.0 Hz, 1H), 3.82 (s, 1H),2.98 (q, J=8.6 Hz, 1H), 2.12 (ddd, J=9.2, 8.0, 5.6 Hz, 1H), 1.61 (dt,J=8.0, 5.3 Hz, 1H), 1.44 (td, J=8.1, 5.0 Hz, 1H); ¹³C NMR (150 MHz,CDCI₃) δ177.16, 167.92, 137.77, 131.75, 131.25, 131.04, 130.26, 126.94,52.12, 26.48, 21.87, 13.60;

HRMS (ESI-TOF) m/z Calcd for C₁₂H₁₃O₄ ⁺ [M+H]⁺ 221.0808, found 221.0807.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-(5-acetylthiophen-2-yl)cyclopropane-1-carboxylic acid (3u)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=1/1 with 1% v/v of acetic acid). Theproduct was obtained as a pale-yellow solid (65% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IG-3 column, 25% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 1.996 min (minor) and 2.557 min (major), 95:5er);

¹H NMR (600 MHz, CDCI₃) δ7.51 (d, J=3.6 Hz, 1H), 6.89 (dd, J=3.9, 0.9Hz, 1H), 2.66 (q, J=8.1 Hz, 1H), 2.64 (s, 3H), 2.15 (ddd, J=8.9, 7.9,6.0 Hz, 1H), 1.70 (dt, J=7.4, 5.8 Hz, 1H), 1.53 (ddd, J=8.2, 8.0, 5.2Hz); ¹³C NMR (150 MHz, CDCI₃) δ190.70, 175.32, 149.33, 143.15, 132.64,127.86, 26.67, 22.76, 21.24, 14.27;

HRMS (ESI-TOF) m/z Calcd for C₁₀H₁₁O₃S⁺ [M+H]⁺ 211.0423, found 211.0428.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2S)-2-(5-formylfuran-2-yl)cyclopropane-1-carboxylic acid (3v)

Substrate 1 was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=1/1 with 1% v/v of acetic acid). Theproduct was obtained as a pale-yellow solid (67% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® AS-3 column, 10% ^(i)PrOH/CO₂, flow rate 1.0 mL/min,retention time 9.843 min (major) and 11.226 min (minor), 96:4 er);

¹H NMR (600 MHz, CDCI₃) δ9.51 (s, 1H), 7.16 (d, J=3.6 Hz, 1H), 6.35 (dd,J=3.6, 0.5 Hz, 1H), 2.58 (q, J=8.5 Hz, 1H), 2.16 (ddd, J=8.5, 8.0, 6.2Hz, 1H), 1.71 (ddd, J=7.2, 6.0, 5.4 Hz, 1H), 1.54 (ddd, J=8.2, 8.1, 5.1Hz, 1H); ¹³C NMR (150 MHz, CDCI₃) (1C overlapped) δ177.17, 175.16,157.97, 152.09, 111.05, 21.48, 18.88, 12.63;

HRMS (ESI-TOF) m/z Calcd for C₉H₉O₄ ⁺ [M+H]⁺ 181.0495, found 181.0495.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2R)-2-(4-(methoxycarbonyl)phenyl)-1-phenylcyclopropane-1-carboxylicacid (5a)

Substrate 4a was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=2/1 with 1% v/v of acetic acid). Theproduct was obtained as a white solid (76% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® AD-3 column, 20% ^(i)PrOH/CO₂, flow rate 2.0 mL/min,retention time 6.718 min (major) and 8.227 min (minor), 98:2 er);

¹H NMR (600 MHz, CDCI₃) δ7.96 (d, J=7.8 Hz, 2H), 7.44 (d, J=7.2 Hz, 2H),7.38-7.34 (m, 4H), 7.30 (tt, J=7.2, 1.5 Hz, 1H), 3.93 (s, 3H), 2.90 (t,J=8.4 Hz, 1H), 2.28 (dd, J=7.8, 4.8 Hz, 1H), 1.70 (dd, J=9.0, 4.8 Hz,1H); ¹³C NMR (150 MHz, CDCI₃) δ176.30, 167.21, 141.47, 139.46, 130.36,129.53, 129.36, 128.82, 128.54, 127.82, 52.22, 38.01, 34.56, 19.39;

HRMS (ESI-TOF) m/z Calcd for C₁₈H₁₆O₄Na⁺ [M+Na]⁺ 319.0941, found319.0943.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2R)-1-(4-chlorophenyl)-2-(4-(methoxycarbonyl)phenyl)cyclopropane-1-carboxylicacid (5b)

Substrate 4b was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=2/1 with 1% v/v of acetic acid). Theproduct was obtained as a white solid (80% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® AD-3 column, 20% ^(i)PrOH/CO₂, flow rate 2.0 mL/min,retention time 6.030 min (major) and 9.105 min (minor), 99:1 er);

¹H NMR (600 MHz, CDCI₃) δ7.96 (d, J=8.4 Hz, 2H), 7.37 (dt, J=8.4, 2.1Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.32 (dt, J=9.0, 2.2 Hz, 2H), 3.94 (s,3H), 2.85 (t, J=8.4 Hz, 1H), 2.27 (dd, J=7.8, 5.1 Hz, 1H), 1.68 (dd,J=9.0, 5.1, 1H); ¹³C NMR (150 MHz, CDCI₃) δ175.90, 167.17, 141.05,137.89, 133.75, 131.74, 129.56, 129.34, 128.96, 128.73, 52.27, 37.28,34.78, 19.41;

HRMS (ESI-TOF) m/z Calcd for C₁₈H₁₆ClO₄ ⁺ [M+H]⁺ 331.0732, found331.0724.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2R)-1-(3-bromophenyl)-2-(4-(methoxycarbonyl)phenyl)cyclopropane-1-carboxylicacid (5c)

Substrate 4c was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=2/1 with 1% v/v of acetic acid). Theproduct was obtained as a colorless oil (90% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® AD-3 column, 20% ^(i)PrOH/CO₂, flow rate 2.0 mL/min,retention time 6.137 min (major) and 6.920 min (minor), 98:2 er);

¹H NMR (600 MHz, CDCI₃) δ7.96 (d, J=8.4 Hz, 2H), 7.58 (t, J=1.8 Hz, 1H),7.43 (ddd, J=8.1, 1.8, 0.9 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.35 (d,J=7.8 Hz, 2H), 7.22 (t, J=7.8 Hz, 1H), 3.95 (s, 3H), 2.88 (t, J=8.4 Hz,1H), 2.27 (dd, J=7.8, 5.2 Hz, 1H), 1.70 (dd, J=9.1, 5.1 Hz, 1H);¹³C NMR(150 MHz, CDCI₃) δ175.75, 167.16, 141.55, 140.89, 133.39, 131.02,130.07, 129.58, 129.35, 129.17, 129.01, 122.37, 52.28, 37.47, 34.65,19.43.

HRMS (ESI-TOF) m/z Calcd for C₁₈H₁₆BrO₄ ⁺ [M+H]⁺ 375.0226, found375.0237.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2R)-2-(4-(methoxycarbonyl)phenyl)-1-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (5d)

Substrate 4d was arylated following the general arylation procedure(eluent: hexanes/ethyl acetate=2/1 with 1% v/v of acetic acid). Theproduct was obtained as a white oil (85% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® AD-3 column, 20% ^(i)PrOH/CO₂, flow rate 2.0 mL/min,retention time 2.852 min (major) and 3.471 min (minor), 99:1 er);

¹H NMR (600 MHz, CDCI₃) δ7.98 (d, J=7.8 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H),7.57 (d, J=8.4 Hz, 2H), 7.38 (d, J=7.8 Hz, 2H), 3.94 (s, 3H), 2.91 (t,J=8.4 Hz, 1H), 2.34 (dd, J=7.5, 5.2 Hz, 1H), 1.74 (d, J=9.0, 5.4 Hz,1H); ¹³C NMR (150 MHz, CDCI₃) δ175.04, 167.13, 143.21, 140.78, 130.80,130.10 (q, J=33 Hz), 129.78, 129.36, 129.13, 125.56 (q, J=4.0 Hz),124.13 (q, J=272 Hz) 52.30, 37.54, 34.63, 19.38; ¹⁹F NMR (376 MHz,CDCI₃) δ-62.84 (s, 3F);

HRMS (ESI-TOF) m/z Calcd for C₁₉H₁₆F₃O₄ ⁺ [M+H]⁺ 365.0995, found365.0994.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2R)-1-ethyl-2-(4-(methoxycarbonyl)phenyl)cyclopropane-1-carboxylicacid (5e)

Substrate 4e was arylated following the general arylation procedureexcept at 60° C. (eluent: hexanes/ethyl acetate=2/1 with 1% v/v ofacetic acid). The product was obtained as a pale-yellow solid (71%yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IA-3 column, 20% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 1.595 min (major) and 1.873 min (minor), 95:5er);

¹H NMR (600 MHz, CDCI₃) δ7.90 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H),3.90 (s, 3H), 2.40 (t, J=8.1 Hz, 1H), 2.04-1.98 (m, 1H), 1.88 (dd,J=7.2, 5.4 Hz, 1H), 1.46-1.40 (m, 1H), 1.18 (dd, J=8.4, 4.8 Hz, 1H),1.05 (t, J=7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCI₃) δ177.71, 167.26,142.28, 129.32, 129.22, 128.42, 52.13, 34.30, 33.52, 28.64, 18.69,11.93;

HRMS (ESI-TOF) m/z Calcd for C₁₄H₁₇O₄ ⁺ [M+H]⁺ 249.1121, found 249.1124.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2R)-1-butyl-2-(4-(methoxycarbonyl)phenyl)cyclopropane-1-carboxylicacid (5f)

Substrate 4f was arylated following the general arylation procedureexcept at 60° C. (eluent: hexanes/ethyl acetate=2/1 with 1% v/v ofacetic acid). The product was obtained as a pale-yellow solid (76%yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® AD-3 column, 20% ^(i)PrOH/CO₂, flow rate 2.0 mL/min,retention time 3.332 min (major) and 3.850 min (minor), 95:5 er);

¹H NMR (600 MHz, CDCI₃) δ7.90 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H),3.90 (s, 3H), 2.39 (t, J=8.1 Hz, 1H), 2.07-2.02 (m, 1H), 1.89 (dd,J=7.2, 5.4 Hz, 1H), 1.52-1.40 (m, 2H), 1.36-1.30 (m, 3H), 1.19 (dd,J=8.6, 5.1 Hz, 1H), 0.91 (t, J=7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCI₃)δ177.47, 167.25, 142.27, 129.33, 129.20, 128.44, 52.14, 35.47, 33.60,33.39, 29.93, 22.90, 18.79, 14.12;

HRMS (ESI-TOF) m/z Calcd for C₁₆H₂₀O₄ ⁺ [M+H]⁺ 277.1434, found 277.1437.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2R)-2-(4-(methoxycarbonyl)phenyl)-1-(3-phenylpropyl)cyclopropane-1-carboxylicacid (5g)

Substrate 4g was arylated following the general arylation procedureexcept at 60° C. (eluent: hexanes/ethyl acetate=2/1 with 1% v/v ofacetic acid). The product was obtained as a pale-yellow oil (58% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® AD-3 column, 20% ^(i)PrOH/CO₂, flow rate 2.0 mL/min,retention time 7.925 min (major) and 9.066 min (minor), 96:4 er);

¹H NMR (600 MHz, CDCI₃) δ7.89 (d, J=9.4 Hz, 2H), 7.28 (t, J=8.1 Hz, 2H),7.22-7.17 (m, 5H), 3.89 (s, 3H), 2.63 (t, J=7.8 Hz, 2H) 2.36 (d, J=7.5Hz, 1H), 2.08-2.02 (m, 1H), 1.90-1.80 (m, 3H), 1.41-1.36 (m 1H), 1.67(dd, J=8.4, 4.8 Hz, 1H); ¹³C NMR (150 MHz, CDCI₃) δ177.46, 167.23,142.14, 142.07, 129.33, 129.22, 129.19, 128.49, 128.47, 125.95, 52.14,35.95, 35.33, 33.70, 33.14, 29.35, 18.95;

HRMS (ESI-TOF) m/z Calcd for C₂₁H₂₃O₄ ⁺ [M+H]⁺ 339.1591, found 339.1595.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2R)-1-(5-chloropentyl)-2-(4-(methoxycarbonyl)phenyl)cyclopropane-1-carboxylicacid (5h)

Substrate 4h was arylated following the general arylation procedureexcept at 60° C. (eluent: hexanes/ethyl acetate=2/1 with 1% v/v ofacetic acid). The product was obtained as a pale-yellow oil (80% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® AD-3 column, 20% ^(i)PrOH/CO₂, flow rate 2.0 mL/min,retention time 4.610 min (major) and 5.459 min (minor), 96:4 er);

¹H NMR (600 MHz, CDCI₃) δ7.90 (d, J=8.4 Hz, 2H), 7.23 (d, J=7.8 Hz, 2H),3.91 (s, 3H), 3.54 (t, J=6.6 Hz, 2H), 2.40 (t, J=8.1 Hz, 1H), 2.08-2.04(m, 1H), 1.91 (dd, J=7.2, 5.4 Hz, 1H), 1.79 (p, J=6.7 Hz, 2H), 1.59-1.43(m, 4H), 1.38-1.32 (m, 1H), 1.21 (dd, J=8.7, 5.0 Hz, 1H); ¹³C NMR (150MHz, CDCI₃) δ177.17, 167.23, 142.05, 129.36, 129.23, 128.54, 52.18,45.15, 35.59, 33.69, 33.17, 32.54, 27.07, 27.02, 18.89;

HRMS (ESI-TOF) m/z Calcd for C₁₇H₂₂ClO₄ ⁺ [M+H]⁺ 325.1201, found325.1205.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1S,2R)-1-benzyl-2-(4-(methoxycarbonyl)phenyl)cyclopropane-1-carboxylicacid (5i)

Substrate 4i was arylated following the general arylation procedureexcept using AgOAc (3.0 equiv) and NaHCO₃ (1.5 equiv) instead of Ag₂CO₃and Na₂CO₃ at 60° C. (eluent: hexanes/ethyl acetate=2/1 with 1% v/v ofacetic acid). The product was obtained as a pale-yellow solid (63%yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® AS-3 column, 20% ^(i)PrOH/CO₂, flow rate 2.0 mL/min,retention time 2.409 min (major) and 2.993 min (minor), 96:4 er);

¹H NMR (600 MHz, CDCI₃) δ7.89 (d, J=8.4 Hz, 2H), 7.31-7.28 (m, 2H),7.24-7.20 (m, 5H), 3.91 (s, 3H), 3.49 (d, J=15.0 Hz, 1H), 2.82 (d,J=15.0 Hz, 1H), 2.47 (t, J=8.1 Hz, 1H), 1.98 (dd, J=7.2, 5.4 Hz, 1H),1.33 (dd, J=8.7, 5.3 Hz, 1H); ¹³C NMR (150 MHz, CDCI₃) δ176.91, 167.22,141.86, 138.65, 129.38, 129.34, 129.21, 128.53, 126.73, 52.17, 39.71,33.48, 32.89, 18.00;

HRMS (ESI-TOF) m/z Calcd for C₁₉H₁₉O₄ ⁺ [M+H]⁺ 311.1278, found 311.1283.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1S,2R)-1-(4-fluorobenzyl)-2-(4-(methoxycarbonyl)phenyl)cyclopropane-1-carboxylicacid (5j)

Substrate 4j was arylated following the general arylation procedureexcept using AgOAc (3.0 equiv) and NaHCO₃ (1.5 equiv) instead of Ag₂CO₃and Na₂CO₃ at 60° C. (eluent: hexanes/ethyl acetate=2/1 with 1% v/v ofacetic acid). The product was obtained as a pale-yellow solid (64%yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® AS-3 column, 20% ^(i)PrOH/CO₂, flow rate 2.0 mL/min,retention time 2.211 min (major) and 2.593 min (minor), 96:4 er);

¹H NMR (600 MHz, CDCI₃) δ7.89 (d, J=8.4 Hz, 2H), 7.21-7.18 (m, 4H), 6.97(t, J=8.7 Hz, 2H), 3.91 (s, 3H), 3.45 (d, J=14.4 Hz, 1H), 2.74 (d,J=14.4 Hz, 1H), 2.47 (t, J=8.2 Hz, 1H) 1.98 (t, J=6.3 Hz, 1H), 1.33 (dd,J=8.7, 5.3 Hz, 1H) ; ¹³C NMR (150 MHz, CDCI₃) δ176.95, 167.19, 161.85(d, J=243 Hz), 141.67, 134.43 (d, J=3 Hz), 130.69 (d, J=10 Hz), 129.38,129.17, 128.65, 115.33 (d, J=21 Hz), 52.19, 39.10, 33.67, 32.98, 18.11;¹⁹F NMR (376 MHz, CDCI₃) δ-116.67 (s, 1F);

HRMS (ESI-TOF) m/z Calcd for C₁₉H₁₈FO₄ ⁺ [M+H]⁺ 329.1184, found329.1185.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2R)-1-((benzyloxy)methyl)-2-(4-(methoxycarbonyl)phenyl)cyclopropane-1-carboxylicacid (5k)

Substrate 4k was arylated following the general arylation (eluent:hexanes/ethyl acetate=2/1 with 1% v/v of acetic acid). The product wasobtained as a pale-yellow solid (65% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® AS-3 column, 20% ^(i)PrOH/CO₂, flow rate 2.0 mL/min,retention time 2.840 min (major) and 3.398 min (minor), 96:4 er);

¹H NMR (600 MHz, CDCI₃) δ7.91 (d, J=7.8 Hz, 2H), 7.37-7.33 (m, 4H),7.32-7.29 (m, 1H), 7.26 (d, J=8.4 Hz, 2H), 4.60 (s, 2H), 3.89 (s, 3H),3.86 (d, J=10.2 Hz, 1H), 3.63 (d, J=10.2 Hz, 1H), 2.59 (t, J=8.4 Hz,1H), 1.99 (dd, J=7.7, 5.3 Hz, 1H), 1.42 (dd, J=8.9, 5.2 Hz, 1H); ¹³C NMR(150 MHz, CDCI₃) δ175.16, 167.16, 141.29, 137.80, 129.44, 129.31,128.77, 128.64, 128.01, 127.88, 73.38, 72.12, 52.16, 32.99, 31.28,16.86.

HRMS (ESI-TOF) m/z Calcd for C₂₀H₂₁O₅ ⁺ [M+H]⁺ 341.1383, found 341.1383.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

(1R,2R)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-(4-(methoxycarbonyl)phenyl)cyclopropane-1-carboxylic acid (5l)

Substrate 4l was arylated following the general arylation (eluent:hexanes/ethyl acetate=1/1 with 1% v/v of acetic acid). The product wasobtained as a white solid (71% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IC column, 30% ^(i)PrOH/CO₂, flow rate 2.0 mL/min, retentiontime 4.593 min (major) and 6.826 min (minor), 98:2 er);

¹H NMR (600 MHz, CDCI₃) δ7.89 (d, J=8.4 Hz, 2H), 7.87-7.84 (m, 2H),7.75-7.72 (m, 2H), 7.27 (d, J=8.4 Hz, 2H), 4.24 (d, J=14.6 Hz, 1H), 4.50(d, J=14.6 Hz, 1H), 3.90 (s, 3H), 2.79 (t, J=8.3 Hz, 1H), 1.99 (dd,J=7.5, 5.5 Hz, 1H), 1.51 (dd, J=8.9, 5.6 Hz, 1H); ¹³C NMR (150 MHz,CDCI₃) δ168.48, 167.15, 140.94, 134.32, 132.01, 129.42, 129.28, 128.87,123.67, 60.57, 52.18, 41.45, 32.88, 17.04;

HRMS (ESI-TOF) m/z Calcd for C₂₁H₁₈NO₆ ⁺ [M+H]⁺ 380.1129, found380.1136.

The absolute stereochemistry was assigned based on comparing the opticalrotation of 3s with literature.

Enantioselective Arylation of 2-Aminoisobutyric Acid

General procedure for enantioselective arylation ofcyclopropanecarboxylic acid: A 2-dram vial equipped with a magnetic stirbar was charged with phthalyl-protect 2-aminoisobutyric acid (23.3 mg,0.10 mmol), Pd(OAc)2 (2.2 mg, 10 mol %), L1 (4.4 mg, 20 mol %), AgOAc(50.0 mg, 0.30 mmol) and NaHCO₃ (12.6 mg, 0.15 mmol). Aryl iodide (0.25mmol) was then added. Subsequently, HFIP (1.0 mL) was injected, and thevial was capped and closed tightly. The reaction mixture was thenstirred at 80° C. for 24 h. The mixture was allowed to cool to roomtemperature and acetic acid (0.05 ml) was added. Then, the mixture waspassed through a pad of Celite with ethyl acetate as the eluent toremove any insoluble precipitate. The resulting solution wasconcentrated.

For compound isolated as an acid: The residual mixture was dissolvedwith a minimal amount of acetone and loaded onto a preparative TLCplate. The pure acid product was then isolated using preparative TLCwith ethyl acetate/hexanes(1/1) with 1% w/w acetic acid as the eluent.

For compound isolated as an ester: The residual mixture was dissolved in0.5 ml DMF. To the solution Cs₂CO₃ (99.7 mg, 0.3 mmol) and Mel (71.0 mg,0.50 mmol, 31 μL) was added. The mixture was stirred at room temperaturefor 3 h and then was diluted with water followed by extraction withethyl acetate. The organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. The residual mixture was dissolved with a minimalamount of acetone and loaded onto a preparative TLC plate. The pureester product was then isolated using preparative TLC with ethylacetate/toluene (1/20) as the eluent.

(S)-2-(1,3-dioxoisoindolin-2-yl)-3-(4-(methoxycarbonyl)phenyl)-2-methylpropanoicacid (7a)

Substrate 6 was arylated following the general arylation procedure. Theproduct was isolated as acid and was obtained as a pale-yellow oil (65%yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IG-3 column, 25% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 3.813 min (minor) and 4.373 min (major), 86:14er);

¹H NMR (600 MHz, CDCI₃) δ7.85 (d, J=7.8 Hz, 2H), 7.78-7.76 (m, 2H),7.72-7.70 (m, 2H), 7.13 (d, J=8.4 Hz, 2H), 3.86 (s, 3H), 3.83 (d, J=13.8Hz, 1H), 3.27 (d, J=13.8, 1H), 1.95 (s, 3H); ¹³C NMR (150 MHz, CDCI₃)δ168.45, 167.06, 141.11, 134.42, 131.45, 130.65, 129.69, 129.12, 123.52,63.71, 52.19, 41.05, 21.97;

HRMS (ESI-TOF) m/z Calcd for C₂₀H₁₈NO₆ ⁺ [M+H]⁺ 368.1129, found368.1131.

The absolute stereochemistry was assigned based on the X-raycrystallographic data of compounds 7f.

Methyl(S)-2-(1,3-dioxoisoindolin-2-yl)-2-methyl-3-(4-(trifluoromethyl)phenyl)propanoate (7b)

Substrate 6 was arylated following the general arylation procedure. Theproduct was isolated as ester and was obtained as a colorless oil (67%yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® AD-3 column, 3% ^(i)PrOH/CO₂, flow rate 1.0 mL/min,retention time 14.292 min (major) and 15.855 min (minor), 87:13 er);

¹H NMR (600 MHz, CDCI₃) δ7.90-7.77 (m, 2H), 7.75-7.71 (m, 2H), 7.43 (d,J=7.8 Hz, 2H), 7.19 (d, J=7.8 Hz, 2H), 3.84 (d, J=13.8 Hz, 1H), 3.75 (s,3H), 3.34 (d, J=13.8 Hz, 1H), 1.90 (s, 3H); ¹³C NMR (150 MHz, CDCI₃)δ172.62, 168.44, 140.01 (q, J=1.1 Hz), 134.43, 131.53, 130.96, 129.52(q, J=32 Hz), 125.24 (q, J=3.5 Hz), 124.25 (q, J=270 Hz), 123.46, 63.86,52.92, 41.32, 22.10; ¹⁹F NMR (376 MHz, CDCI₃) δ-62.75 (s, 3F);

HRMS (ESI-TOF) m/z Calcd for C₂₁H₁₇F₃NO₄ ⁺ [M+H]⁺ 392.1104, found392.1106.

The absolute stereochemistry was assigned based on the X-raycrystallographic data of compounds 7f.

Methyl(S)-2-(1,3-dioxoisoindolin-2-yl)-3-(4-fluorophenyl)-2-methylpropanoate(7c)

Substrate 6 was arylated following the general arylation procedure. Theproduct was isolated as ester and was obtained as a colorless oil (60%yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® OJ-3 column, 5% ^(i)PrOH/CO₂, flow rate 2.0 mL/min,retention time 2.868 min (minor) and 3.419 min (major), 89:11 er);

¹H NMR (600 MHz, CDCI₃) δ7.79-7.76 (m, 2H), 7.73-7.70 (m, 2H), 7.04-7.00(m, 2H), 6.7-6.84 (m, 2H), 3.75 (s, 3H), 3.75 (d, J=14.4 Hz, 1H), 3.23(d, J=14.4 Hz, 1H), 1.88 (s, 3H); ¹³C NMR (150 MHz, CDCI₃) δ172.86,168.47, 162.18 (d, J=244 Hz), 134.32, 132.04 (d, J=9 Hz), 131.59, 131.52(d, J=4 Hz), 123.39, 115.26 (d, J=22 Hz), 64.05, 52.83, 20.65, 22.02;¹⁹F NMR (376 MHz, CDCI₃) δ-115.88 (s, 1F);

HRMS (ESI-TOF) m/z Calcd for C₁₉H₁₇FNO₄ ⁺ [M+H]⁺ 342.1136, found342.1148.

The absolute stereochemistry was assigned based on the X-raycrystallographic data of compounds 7f.

Methyl(S)-3-(4-chlorophenyl)-2-(1,3-dioxoisoindolin-2-yl)-2-methylpropanoate(7d)

Substrate 6 was arylated following the general arylation procedure. Theproduct was isolated as ester and was obtained as a pale-yellow solid(60% yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® OJ-3 column, 5% ^(i)PrOH/CO₂, flow rate 2.0 mL/min,retention time 3.660 min (minor) and 5.426 min (major), 91:9 er);

¹H NMR (600 MHz, CDCI₃) δ7.80-7.76 (m, 2H), 7.74-7.71 (m, 2H), 7.14 (dt,J=8.4, 2.1 Hz, 2H), 6.99 (dt, J=8.4, 2.1 Hz, 2H), 3.75 (d, J=13.8 Hz,1H), 3.75 (s, 3H), 3.24 (d, J=13.8 Hz, 1H), 1.88 (s, 3H); ¹³C NMR (150MHz, CDCI₃) δ172.78, 168.47, 134.35, 134.31, 133.24, 131.89, 131.58,128.54, 123.43, 63.96, 52.87, 40.84, 22.03;

HRMS (ESI-TOF) m/z Calcd for C₁₉H₁₇ClNO₄ ⁺ [M+H]⁺ 358.0841, found358.0841.

The absolute stereochemistry was assigned based on the X-raycrystallographic data of compounds 7f.

Methyl(S)-3-(4-bromophenyl)-2-(1,3-dioxoisoindolin-2-yl)-2-methylpropanoate(7e)

Substrate 6 was arylated following the general arylation procedure. Theproduct was isolated as ester and was obtained as a white solid (65%yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® OJ-3 column, 5% ^(i)PrOH/CO₂, flow rate 2.0 mL/min,retention time 4.313 min (minor) and 6.771 min (major), 92:8 er);

¹H NMR (600 MHz, CDCI₃) δ7.80-7.77 (m, 2H), 7.74-7.71 (m, 2H), 7.29 (d,J=7.8 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 3.75-3.72 (m, 4H), 3.22 (d,J=13.8 Hz, 1H), 1.88 (s, 3H); ¹³C NMR (150 MHz, CDCI₃) δ172.76, 168.46,134.82, 134.36, 132.27, 131.57, 131.49, 123.44, 121.39, 63.89, 52.88,40.91, 22.02;

HRMS (ESI-TOF) m/z Calcd for C₁₉H₁₇BrNO₄ ⁺ [M+H]⁺ 402.0335, found402.0341.

The absolute stereochemistry was assigned based on the X-raycrystallographic data of compounds 7f.

Methyl (S)-2-(1,3-dioxoisoindolin-2-yl)-2-methyl-3-(p-tolyl)propanoate(7f)

Substrate 6 was arylated following the general arylation procedure. Theproduct was isolated as ester and was obtained as a white solid (65%yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® OJ-3 column, 5% ^(i)PrOH/CO₂, flow rate 2.0 mL/min,retention time 3.360 min (minor) and 5.523 min (major), 93:7 er);

¹H NMR (600 MHz, CDCI₃) δ7.79-7.76 (m, 2H), 7.72-7.69 (m, 2H), 6.96 (d,J=7.8 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 3.74 (d, J=13.8 Hz, 1H), 3.74 (s,3H), 3.22 (d, J=13.8 Hz, 1H), 2.26 (s, 3H), 1.87 (s, 3H); ¹³C NMR (150MHz, CDCI₃) δ173.08, 168.55, 136.71, 134.19, 132.58, 131.73, 130.46,129.06, 123.33, 64.28, 52.76, 40.96, 21.89, 21.20;

HRMS (ESI-TOF) m/z Calcd for C₂₀H₂₀NO₄ ⁺ [M+H]⁺ 338.1387, found338.1399.

The absolute stereochemistry was assigned based on the X-raycrystallographic data of compounds 7f.

(S)-2-(1,3-dioxoisoindolin-2-yl)-3-(3-(methoxycarbonyl)phenyl)-2-methylpropanoicacid (7g)

Substrate 6 was arylated following the general arylation procedure. Theproduct was isolated as acid and was obtained as a colorless oil (67%yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® IG-3 column, 25% (MeOH containing 0.5% HCO₂H)/CO₂, flow rate4 mL/min, retention time 3.052 min (minor) and 3.494 min (major), 86:14er);

¹H NMR (600 MHz, CDCI₃) δ7.86-7.84 (m, 1H), 7.75-7.72 (m, 2H), 7.70-7.68(m, 3H), 7.24-7.23 (m, 2H), 3.77 (d, J=13.8 Hz, 1H), 3.72 (s, 3H), 3.22(d, J=13.8 Hz, 1H), 1.90 (s, 3H); ¹³C NMR (150 MHz, CDCI₃) δ167.96,166.31, 135.64, 134.49, 133.65, 129.58, 127.92, 127.88, 122.80, 63.34,51.52, 40.20, 21.26;¹³C NMR (150 MHz, CDCI₃) δ176.90, 168.56, 166.91,136.24, 135.09, 134.25, 131.63, 131.58, 130.18, 128.52, 128.49, 123.40,63.94, 52.12, 40.80, 21.86.

HRMS (ESI-TOF) m/z Calcd for C₂₀H₁₈NO₆ ⁺ [M+H]⁺ 368.1129, found368.1136.

The absolute stereochemistry was assigned based on the X-raycrystallographic data of compounds 7f.

Methyl (S)-2-(1,3-dioxoisoindolin-2-yl)-2-methyl-3-(m-tolyl)propanoate(7h)

Substrate 6 was arylated following the general arylation procedure. Theproduct was isolated as ester and was obtained as a colorless oil (65%yield).

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® OJ-3 column, 5% ^(i)PrOH/CO₂, flow rate 2.0 mL/min,retention time 3.367 min (minor) and 4.225 min (major), 92:8 er);

¹H NMR (600 MHz, CDCI₃) δ7.79-7.75 (m, 2H), 7.72-7.69 (m, 2H), 7.05 (t,J=7.5 Hz, 1H), 6.98 (d, J=7.2 Hz, 1H), 6.84 (d, J=7.2 Hz, 1H), 6.81 (s,1H), 3.75 (s, 3H), 3.73 (d, J=13.8 Hz, 1H), 3.20 (d, J=13.8 Hz, 1H),2.12 (s, 3H), 1.88 (s, 3H);¹³C NMR (150 MHz, CDCI₃) δ173.11, 168.53,137.80, 135.67, 134.19, 131.74, 131.49, 128.20, 127.90, 127.63, 123.29,64.23, 52.77, 41.27, 21.95, 21.30.

HRMS (ESI-TOF) m/z Calcd for C₂₀H₂₀NO₄ ⁺ [M+H]⁺ 338.1387, found338.1397.

The absolute stereochemistry was assigned based on the X-raycrystallographic data of compounds 7f.

Enantioselective Arylation of Drug Candidate

A 2-dram vial equipped with a magnetic stir bar was charged withPd(OAc)2 (4.4 mg, 10 mol %) and L1 (8.8 mg, 20 mol %) in HFIP (0.25 ml).To the solution was added 8 (65.0 mg, 0.2 mmol). Ag₂CO₃ (82.7 mg, 0.30mmol), Na₂CO₃ (31.8 mg, 0.30 mmol) and 2a (104.8 mg, 0.40 mmol) was thenadded. Subsequently, the vial was capped and closed tightly. Thereaction mixture was then stirred at the rate of 200 rpm at 80° C. for16 h. After being allowed to cool to room temperature, the mixture wasdiluted with ethyl acetate, and 0.1 ml of acetic acid was then added.The mixture was passed through a pad of Celite with ethyl acetate as theeluent to remove any insoluble precipitate. The resulting solution wasconcentrated, and the residual mixture was dissolved with a minimalamount of acetone and loaded onto a preparative TLC plate. The pureproduct was then isolated using preparative TLC with ethyl acetate andhexanes (1/1) as the eluent and 1% v/v of acetic acid as an additive.The product was obtained as a white solid (90% yield)

(1R,2R)-1-(3′,4′-dichloro-2-fluoro-[1,1-biphenyl]-4-yl)-2-(4-(methoxycarbonyl)phenyl)cyclopropane-1-carboxylic acid (9)

The enantiomeric purity of the substrate was determined by SFC analysis(CHIRALPAK® AD-3 column, 30% ^(i)PrOH/CO₂, flow rate 2.0 mL/min,retention time 6.029 min (major) and 7.129 min (minor), 97:3 er);

¹H NMR (600 MHz, CDCI₃) δ7.98 (d, J =8.4, 2H), 7.63 (s, 1H), 7.51 (d,J=8.4 Hz, 1), 7.38-7.36 (m, 4H), 7.30 (d, J=7.8 Hz, 1H), 7.26 (d, J=10.8Hz, 1H), 3.94 (s, 3H), 2.92 (t, J=8.4 Hz, 1H), 2.32 (dd, J=6.9, 5.7 Hz,1H), 1.75 (dd, J=8.7, 5.1 Hz, 1H) ; ¹³C NMR (150 MHz, CDCI₃) δ175.21,167.13, 159.28 (d, J=243 Hz), 141.66 (d, J=8 Hz), 140.79, 135.32,132.80, 132.25, 130.88 (d, J=3 Hz), 130.61, 130.41 (d, J=3 Hz), 129.62,129.36, 129.12, 128.38 (d, J=3 Hz), 126.47 (d, J=3 Hz), 126.24 (d, J=12Hz), 118.33 (d, J=22 Hz), 52.31, 37.29, 34.85, 19.59; ¹⁹F NMR (376 MHz,CDCI₃) δ-117.31 (s, 1F); HRMS (ESI-TOF) m/z Calcd for C₂₄H₁₈Cl₂FO₄ ⁺[M+H]⁺ 459.0561, found 459.0564.

X-Ray Crystallographic Data of Compounds

TABLE S1 Crystal data and structure refinement for 7f. CDCC number1833926 Empirical formula C₂₀H₁₉NO₄ Formula weight 337.36 Temperature100.0K Wavelength 1.54178 Å Crystal system Monoclinic Space group P 21Unit cell dimensions a = 10.4618(5) Å a = 90°. b = 6.6429(3) Å b =112.484(2)°. c = 12.8407(6) Å g = 90°. Volume 824.55(7) Å³ Z 2 Density(calculated) 1.359 Mg/m³ Absorption coefficient 0.776 mm⁻¹ F(000) 356Crystal size 0.28 × 0.2 × 0.18 mm³ Theta range for data collection 3.725to 69.101°. Index ranges −12 <= h <= 12, −8 <= k <= 8, −15 <= l <= 15Reflections collected 11626 Independent reflections 3042 [R(int) =0.0431] Completeness to theta = 67.679° 100.0% Absorption correctionSemi-empirical from equivalents Max. and min. transmission 0.7531 and0.6776 Refinement method Full-matrix least-squares on F²Data/restraints/parameters 3042/1/229 Goodness-of-fit on F² 1.076 FinalR indices [I > 2sigma(I)] R1 = 0.0351, wR2 = 0.0893 R indices (all data)R1 = 0.0367, wR2 = 0.0909 Absolute structure parameter −0.05(12)Extinction coefficient n/a Largest diff. peak and hole 0.285 and −0.165e.Å-3

-   1. Xiao, K.-J.; Lin, D. W.; Miura, M.; Zhu, R.-Y.; Gong, w. Wasa,    M.; Yu, J.-Q. J. Am. Chem. Soc. 2014, 136, 8138.-   2. Li, J.; Luo, S.; Cheng, J. P. J. Org. Chem. 2009, 74, 1747.-   3. Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005, 127, 10504.-   4. Nagamine, T.; Inomata, K.; Endo, Y. Heterocycles 2008, 76, 1191.-   5. Wasa, M.; Engle, K. M.; Lin, D. W.; Yoo, E. J.; Yu, J.-Q. J. Am.    Chem. Soc. 2011, 133, 19598.-   6. Santen Pharmaceutical Co., Ltd EP2119703 2009, A1.-   7. Wyeth US2008/255192 2008, A1-   8. Giri, R.; Wasa, M.; Breazzano, S. P.; Yu, J.-Q. Org. Lett. 2006,    8, 5685.-   9. Jahngen, E. G. E.; Phillips, D.; Kobelski, R. J.; Demko, D. M. J.    Org. Chem. 1983, 48, 2472.-   10. Chen, K.; Li, Z.-W.; Shen, P.-X.; Zhao, H.-W.; Shi, Z.-J. Chem.    Eur. J. 2015, 21, 7389.-   11. Schiefer, I. T.; Abdul-Hay, S.; Wang, H.; Vanni, M.; Qin, Z.;    Thatcher, G. R. J. J. Med. Chem. 2011, 54, 2293.-   12. Elling, G. R.; Hahn, R. C.; Schwab, G. J. Am. Chem. Soc. 1973,    17, 5659.

All patents and publications referred to herein are incorporated byreference herein to the same extent as if each individual publicationwas specifically and individually indicated to be incorporated byreference in its entirety.

What is claimed is:
 1. A method of stereoselective arylation of aβ-carbon atom of a cyclopropanecarboxylic acid having a β-hydrogen atom,the cyclopropropanecarboxylic acid having either an α-substituent orhaving no α-substituent, comprising contacting thecyclopropanecarboxylic acid and an aryl iodide in the presence of acatalytic quantity of a Pd(II) salt, a molar equivalent or more on anAg(I) basis of an Ag(I) salt, and a molar equivalent or more of a base,in 1,1,1,3,3,3-hexafluoroisopropanol solvent, in the presence of ansingle enantiomer, either (R) or (S), of an acetyl-protected aminoethylamine (APAA) ligand of formula

wherein Ac is acetyl, each R is independently selected methyl or ethyl,or the two R groups together with the nitrogen atom to which they arebonded form a 4- to 6-membered heterocyclyl ring; and wherein R¹ is anunsubstituted or substituted benzyl group, or wherein R¹ is a(C₃-C₄)-alkyl group; to stereoselectively provide aβ-aryl-cyclopropanecarboxylic acid, wherein the arylated β-carbon atomof the β-aryl-cyclopropanecarboxylic acid product, when no α-substituentis present is of an (R) or (S) single enantiomeric configuration,respectively, and when an α-substituent is present is of an (S) or (R)single enantiomeric configuration, respectively; the aryl groupintroduced being disposed cis to the carboxylic acid group of thecyclopropanecarboxylic acid.
 2. The method of claim 1 wherein the APAAligand is of formula


3. The method of claim 1 wherein the Pd(II) salt is Pd(OAc)₂.
 4. Themethod of claim 1 wherein the carbonate base is Na₂CO₃, or wherein theAg(I) salt is Ag₂CO₃, or both.
 5. The method of claim 1 wherein thePd(II) salt is present at about 10 mole %, the ligand is present atabout 20 mole %, or both.
 6. A method of stereoselective arylation of aβ-carbon atom of 2-phthalimidoisobutryic acid, comprising contacting the2-phthalimidoisobutryic acid and an aryl iodide in the presence of acatalytic quantity of a Pd(II) salt, a molar equivalent or more on anAg(I) basis of an Ag(I) salt, and a molar equivalent or more of a base,in 1,1,1,3,3,3-hexafluoroisopropanol solvent, in the presence of ansingle enantiomer, either (R) or (S), of an acetyl-protected aminoethylamine (APAA) ligand of formula

wherein Ac is acetyl, each R is independently selected methyl or ethyl,or the two R groups together with the nitrogen atom to which they arebonded form a 4- to 6-membered heterocyclyl ring; and wherein R¹ is anunsubstituted or substituted benzyl group, or wherein R¹ is a(C₃-C₄)-alkyl group; to stereoselectively provide aβ-aryl-2-phthalimidoisobutryic acid, wherein theβ-aryl-2-phthalimidoisobutryic acid product is of an (R) or (S) singleenantiomeric configuration, respectively.
 7. The method of claim 6wherein the APAA ligand is of formula


8. The method of claim 6 wherein the Pd(II) salt is Pd(OAc)₂.
 9. Themethod of claim 6 wherein the carbonate base is Na₂CO₃, or wherein theAg(I) salt is Ag₂CO₃, or both.
 10. The method of claim 6 wherein thePd(II) salt is present at about 10 mole %, the ligand is present atabout 20 mole %, or both.